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Back to Journals » Journal of Inflammation Research » Volume 17
Ferroptosis in Osteoarthritis: Current Understanding
Authors Liu Y, Zhang Z, Fang Y, Liu C, Zhang H
Received 25 August 2024
Accepted for publication 17 October 2024
Published 7 November 2024 Volume 2024:17 Pages 8471—8486
DOI https://doi.org/10.2147/JIR.S493001
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Ning Quan
Yikai Liu,1,2 Zian Zhang,2 Yuan Fang,2 Chang Liu,2 Haining Zhang2
1Department of Orthopaedics and Traumatology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People’s Republic of China; 2Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China
Correspondence: Haining Zhang, Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China, Tel +86-18661800365, Email [email protected]
Abstract: Osteoarthritis (OA) is a prevalent degenerative disease in elderly people that is characterized by cartilage loss and abrasion, leading to joint pain and dysfunction. The aetiology of OA is complicated and includes abnormal mechanical stress, a mild inflammatory environment, chondrocyte senescence and apoptosis, and changes in chondrocyte metabolism. Ferroptosis is a regulated cell death modality characterized by the excessive accumulation of lipid peroxidation and mitochondrial dysfunction. The role of ferroptosis in OA pathogenesis has aroused researchers’ attention in the past two years, and there is mounting evidence indicating that ferroptosis is destructive. However, the impact of ferroptosis on OA and how the regulators of ferroptosis affect OA development are unclear. Here, we reviewed the current understanding of ferroptosis in OA pathogenesis and summarized several drugs and compounds targeting ferroptosis in OA treatment. The accumulation of intracellular iron, the trigger of Fenton reaction, the excessive production of ROS, the peroxidation of PUFA-PLs, and mitochondrial and membrane damage are involved in chondrocyte ferroptosis. System Xc− and GPX4 are the most important regulators that control ferroptosis. Several compounds, such as DFO and Fer-1, have been proven effective in preventing ferroptosis and slowing OA progression on animal models. Collectively, targeting ferroptosis shows great potential in treating OA.
Keywords: ferroptosis, osteoarthritis, chondrocyte, lipid peroxidation, iron metabolism
Introduction
Osteoarthritis (OA) is a prevalent joint degenerative disease in elderly individuals and is characterized by chronic joint pain and joint dysfunction, imposing a huge burden on life quality and the economy.1 OA is a heterogenous disease with multiple etiologies, initially recognized as a wear-and-tear disease.2,3 However, non-loading joints such as those in the hands can also develop OA, indicating that many other mechanisms play important roles in OA, such as inflammation, dysregulation of chondrocyte metabolism and diet-associated dysbiosis.4–6 The ferroptosis pathway was found to be enriched, and the expression of iron overload-related genes, including FTH1, was elevated in cartilage collected from individuals with hand OA compared to that of healthy donors.7 Chondrocytes are the only cell type within cartilage, whose state is vital for extracellular matrix (ECM) formation and cartilage metabolism. When catabolism exceeds anabolism, cartilage degeneration occurs and OA develops.8 Several studies have reported the roles of chondrocyte apoptosis,9–12 chondrocyte senescence,13–15 chondrocyte hypertrophy,16–18 chondrocyte pyroptosis19–21, and chondrocyte energy metabolism dysfunction22–24 in the development of OA.
Chondrocyte ferroptosis has garnered researchers’ attention in recent years and has been proven to exacerbate cartilage degeneration and the progression of OA. Ferroptosis is a regulated cell death first proposed by Stockwell’s team.25 It is associated with lipid peroxidation and abnormal mitochondrial changes, including morphology, bioenergetics and metabolism.26 During ferroptosis, morphological alterations include diminished or vanished mitochondrial cristae, as well as rupturing and wrinkling of the mitochondrial outer membrane, resulting in intensified mitochondrial staining.27 While the cell membrane is breached, the nucleus remains intact, distinguishing this process from other forms of cell death such as apoptosis.27 Ferroptosis also dynamically regulates key processes of mitochondrial homeostasis such as fission, fusion and mitophagy.28 Over the past decades, ferroptosis has been shown to participate in various diseases and conditions, such as brain injury, Parkinson’s disease, heart injury, tumor suppression and immune functions.29 Recently, the role of ferroptosis in promoting OA development has been reported and treated as a therapeutic target. Increased expression of a disintegrin and metalloproteinase with thrombospondin 5 (ADAMTS5) and matrix metalloproteinase-13 (MMP13) was found in the iron overloaded mice model, indicating that iron overload significantly contributed to cartilage degeneration. A ferroptosis inducer like ferric ammonium citrate (FAC) could increase MMP3 and MMP13 levels in chondrocytes and promote the progression of OA.30,31 The expression of glutathione peroxidase 4 (GPX4), an inhibitory factor of ferroptosis, was significantly lower in osteoarthritic cartilage than in normal cartilage.32 Additionally, the knockdown of GPX4 by AAV-Gpx4 shRNA exacerbated OA in posttraumatic OA mouse model.32 Ferroptosis is closely related to oxidative stress, which is a key factor in OA pathogenesis.13,14 The Fenton reaction in the ferroptosis process could generate ROS and exacerbate oxidative stress,33 and the downregulation of GPX4 could enhance the susceptibility of chondrocytes to oxidative stress through the MAPK/NF-κB pathway.32 Lipid peroxidation has long been associated with OA, and there are increased markers of lipid peroxidation in serum,34 synovial fluid,35 osteoarthritic chondrocytes,36 and synoviocytes.37 Several compounds, such as DFO,31,32,38 Fer-1,32 Icariin,39 and N-acetyl cysteine (NAC),40 have been demonstrated to effectively alleviate OA progression by regulating ferroptosis. Therefore, a deeper understanding of the mechanism of ferroptosis in the pathogenesis of OA has potential significance for exploring new drug targets for OA. In this review, we illustrate the impacts of ferroptosis and lipid peroxidation on OA pathogenesis to identify potential treatments targeting ferroptosis in the future.
The Key Processes in Ferroptosis
The initiation of ferroptosis normally included the following processes, the accumulation of intracellular iron, the triggering of Fenton reaction, excessive production of ROS, the integration of polyunsaturated fatty acids (PUFAs) into phospholipids (PLs) and the peroxidation of PUFA-PLs, and finally mitochondrial and membrane damage. They are as follows.
Intracellular Iron Accumulation
Fe2+ in food is taken up by enterocytes via divalent metal-ion transporter 1 (DMT1) and secreted into the blood via ferroportin (FPN).41 Fe2+ is oxidized into Fe3+ by ferroxidase and hephaestin,42–44 and Fe3+ binds with transferrin (Tf), circulates through the body, and is delivered to multiple organs and tissues.42 After Tf binds to the transferrin receptor 1 (TfR1) on the cell membrane, Fe3+ bounded with Tf is absorbed into cells through receptor-mediated endocytosis.42 Low pH in the endosomes can release Fe3+ from Tf and reduce Fe3+ into Fe2+, and then Fe2+ in the endosome is released via DMT1.45 Intracellular iron is primarily bound to ferritin, which consists of ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL) and functions as iron storage.46,47 The degradation of ferritin through autophagy will trigger labile iron overload and contributes to the initiation of ferroptosis, a process known as ferritinophagy.48 NCOA4 functions as a ferritinophagy receptor, which interacts with an arginine residue in the C terminal domain of FTH1, leading to selective degradation of ferritin and increased Fe2+ level in the cytoplasm.49 Under normal conditions, only a small amount of free iron forms the labile iron pool and regulates iron homeostasis.50,51 Fe2+ can be released from the cell via SLC40A1 on the plasma membrane. Excessive intracellular iron levels can lead to reactive oxygen species (ROS) generation via the Fenton reaction, which promotes lipid peroxidation and ferroptosis. Mitochondrial iron accounts for 20–50% of the total intracellular iron depending on the cell type,52 which also contains a free iron pool that participates in the production of mitochondrial ROS.53,54 Factors that promote iron absorption, inhibit iron storage, or restricting iron efflux will lead to lipid peroxidation and ferroptosis55 (Figure 1).
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Figure 1 Iron metabolism. Iron in food is taken up by enterocytes in the form of Fe2+ via DMT1, and secreted into extracellular fluid via FPN. Fe2+ is oxidized into Fe3+ through the catalysis of ferroxidase and hephaestin, and binds with Tf, forming the Tf-Fe3+ complex. The Tf-Fe3+ complex is then circulated to peripheral tissues and cells via blood flow. Tf-Fe3+ is recognized by TfR on the cell membrane and taken up by the cell via endocytosis. Low pH in the endosomes can release Fe3+ from Tf and reduce Fe3+ into Fe2+, and then Fe2+ in the endosome is released out via DMT1. The majority of intracellular iron is bound to ferritin, which consists of FTH1 and FTL and functions as iron storage. Only a small amount of free iron forms the labile iron pool and regulates iron homeostasis. Ferritin can be degraded through NCOA4-mediated autophagy named ferritinophagy, leading to increased Fe2+ level in the cytoplasm. Fe2+ can generate ROS via the Fenton reaction, ultimately resulting in lipid peroxidation. The ROS induce oxidative damage in cell membranes and organelles, as well as disturbances in homeostatic cell signal transduction, including the activation of pro-catabolic MAP kinase (p38 and ERK) signaling and the inhibition of pro-anabolic IGF-1 and BMP7 signaling through the inhibition of PI3K-Akt and Smads, ultimately leading to cell death and cartilage degeneration. DFO can inhibit the free Fe2+-mediated Fenton reaction. Excess Fe2+ is excreted from the cell via SLC40A1. Abbreviations: DMT1, divalent metal-ion transporter 1, a protein that assists in transmembrane transport of Fe2+; FPN, ferroportin, a protein that assists in excreting Fe2+ from cells; Tf, transferrin, a protein that binds with Fe3+ and helps transfer it in the blood; TfR1, transferrin receptor 1, a receptor of Tf-Fe3+ complex on the cell membrane of the peripheral cells; FTL, ferritin light chain, a polypeptide chain combined with FTH1 and stores intracellular iron; FTH1, ferritin heavy chain 1, a polypeptide chain combined with FTL and stores intracellular iron; ROS, reactive oxygen species; DFO, deferoxamine, an iron chelator; SLC40A1, solute carrier family 40 member A1, a protein that assists in excreting Fe2+ from cells. |
Integration of PUFAs into PLs
PUFAs are fatty acids that contain more than one unsaturated bond, such as C=C bonds. Unsaturated C=C bonds grant can be peroxidised. Free PUFAs can be directly synthetized from acetyl-CoA, which is catalysed by acetyl-coenzyme A carboxylase. Then PUFAs are converted into PUFA-CoA by acyl-CoA synthetase long-chain family member 1(ACSL1) and ACSL4, and they bind to PLs via lysophosphatidylcholine acyltransferase 3 (LPCAT3). The conjunction of PUFAs to PLs is vital, because only when PUFA-PLs are oxidized can they break the membrane, and PUFA-OOH alone has no negative effects (Figure 2).
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Figure 2 The process of lipid peroxidation and ferroptosis. System Xc− are composed of two members, SLC7A11 and SLC3A2, which can take up cystine and discharge glutamate from the cell. Intracellular cystine ultimately participates in the synthesis of GPX4, a key negative regulator of ferroptosis. PUFAs are activated by LPCAT3 and ACSL4 and bind to PLs. Then, PUFAs are oxidized into PL-PUFA-OOH by ALOX and oxidants such as Fe2+, ROS, NOXs, and POR. PL-PUFA-OOH ultimately results in membrane oxidative damage and cell death. GPX4 exerts its anti-ferroptotic effect by reducing PL-PUFA-OOH to PL-PUFA-OH. Its activity is inhibited by RSL3, ML162, ML210, and FIN56. Other inhibitors of ferroptosis act by preventing the production of PL-PUFA-OOH, such as FSP1/CoQ10, NADPH, DHODH, MUFA and GCH1/BH4. Moreover, the peroxidized PUFA-OOH tail can be trimmed from the phospholipid by iPLA2β, which can suppress the negative effects of PL-PUFA-OOH. Erastin and sulfasalazine promote ferroptosis by inhibiting the intake of cysteine through System Xc−. RSL3, ML162, ML210 and FIN56 promote ferroptosis by inhibiting the activity of GPX4. Fe2+, POS, NOXs, POR promote ferroptosis by stimulating the production of PL-PUFA-OOH. Conversely, FSP1/CoQ10, NADPH, DHODH and GCH1/BH4 prevent ferroptosis by inhibiting the the production of PL-PUFA-OOH; Finally, Ferrostatin-1 and Liproxstatin-1 prevent ferroptosis by mitigating the detrimental effects of PL-PUFA-OOH on the membrane. Abbreviations: SLC7A11, solute carrier family 7 member 11; GPX4, Glutathione peroxidase 4; PUFA, Polyunsaturated fatty acid; Cys, cysteine; GCLC, glutamate-cysteine ligase catalytic subunit, which transforms cysteine into GGC; GGC, γ-glutamylcysteine, direct precursor of GSH; GS, glutamylcysteine synthase; GSH, glutathione; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; PL, phospholipid; PL-PUFA, the conjunction of PUFAs to PLs; PL-PUFA-OH, the oxidized PL-PUFA; PL-PUFA-OOH, the peroxidized PL-PUFA; ALOXs, lipoxygenases; ROS, reactive oxygen species; POR, cytochrome P450 oxidoreductase; RSL3, RAS-selective-lethal-3; FIN56, ferroptosis-Inducer-56; FSP1, ferroptosis suppressor protein 1; CoQ10, coenzyme Q10; NADPH, nicotinamide adenine dinucleotide phosphate; DHODH, dihydroorotate dehydrogenase; MUFA, monounsaturated fatty acid; GCH1, GTP cyclohydrolase 1; BH4, tetrahydrobiopterin; iPLA2b, phospholipase A2 group VI. |
Peroxidation of PUFA-PLs
The accumulated PUFA-PLs can be oxidized by Fe2+ and endoperoxide compounds such as FINO2. Several Fe2+-dependent enzymes promote the change from PUFA-PL to PUFA-PL-OOH, including lipoxygenases (ALOXs), phosphatidylethanolamine binding protein 1 (PEBP1) and cytochrome p450 oxidoreductase (POR). Additionally, there are several secondary products, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA).56 4-HNE and MDA serve as reliable indicators of lipid peroxidation and ferroptosis in various diseases,57 such as cancer,58 neurodegenerative disease,59 cardiac injury60 acute kidney injury61 and acute lung injury.62 The accumulation of PUFA-PL-OOH can cause stiffening of the endoplasmic reticulum (ER) membrane.63 Mitochondrial ROS can also oxidize PUFA-PLs on mitochondrial membranes, resulting in lipid peroxidation and mitochondrial DNA damage.64 The mitochondrial membrane is affected by the destructive effect of lipid peroxidation products, leading to mitochondrial dysfunction.55 However, the mechanisms through which lipid peroxides break the membranes and cause cell death are still unknown (Figure 2).
Negative Regulators of Ferroptosis
System Xc− and GPX4 are the most important regulators that control ferroptosis. Several typical ferroptosis inducers, including erastin and sulfasalazine, exert their effects by inhibiting ferroptosis.65 Located on the cell membrane, system Xc− is composed of two members, solute carrier family 7 member 11 (SLC7A11) and SLC3A2. System Xc− functions by taking up cystine and discharging glutamate from the cell.66 Cystine and glutamate are used to synthesize GSH and GPX4. GPX4 is a GSH-dependent enzyme and is central to ferroptosis regulation by reducing reactive PUFA-PL-OOH to nonreactive and nonlethal PUFA-PL-OH.65 The reduction of GSH can inactivate GPX4 and trigger Fe2+ for the Fenton reaction, leading to the accumulation of lipid peroxides and ferroptosis.67 Genetic inactivation of GPX4 can induce lipid peroxidation and nonapoptotic cell death,68 which is called ferroptosis. The overexpression of the light chain of system Xc− protects cells from this nonapoptotic cell death.69 Moreover, nuclear factor erythroid 2-related factor 2 (NRF2), an important transcriptional regulator of anti-ferroptotic genes such as GPX4 and System Xc−, can prevent lipid peroxidation and the accumulation of free iron.70 As a stress-inducible transcription factor, NRF2 translocates to the nucleus to promote the transcription of antioxidant response element (ARE)-containing gene, most of which are responsible for preventing lipid peroxidation and ferroptosis.70 NRF2 also maintains cellular iron homeostasis by controlling HERC2 (E3 ubiquitin ligase for NCOA4 and FBXL5) and VAMP8 (mediates autophagosome-lysosome fusion).71
There are other regulators that counteract ferroptosis and are independent of GPX4, such as ferroptosis suppressor protein 1 (FSP1)/ coenzyme Q10 (CoQ10), dihydroorotate dehydrogenase (DHODH), and GTP cyclohydrolase 1 (GCH1)/tetrahydrobiopterin (BH4). CoQ10 acts as an another endogenous mechanism against lipid peroxidation in addition to GPX4. FSP1 is responsible for regenerating CoQ10 by using nicotinamide adenine dinucleotide phosphate (NADPH).72 iFSP1 was reported to competitively inhibit FSP1 enzyme activity73 and 3-phenylquinazolinones (icFSP1) was newly identified to inhibit FSP1 by triggering subcellular relocalization of FSP1 from the membrane before ferroptosis induction.74 CoQ10 protects against lipid peroxidation by being oxidized as a substitute for PUFA-PL. The amino acid oxidase interleukin-4-induced-1 (IL4i1), first recognized as a response to IL-4 in B cells, generates indole-3-pyruvate (In3Py), which prevents ferroptosis by clearing radicals and manipulating the relevant gene expression that alleviates ferroptosis.75 GCH1 can generate the antioxidant BH4, whose functions are similar to CoQ10 in preventing lipid peroxidation.76 In addition, GCH1 can restore the level of decreased CoQ10, and eliminate PUFA-PLs, which are the precursors of PUFA-PL-OOHs and lead to ferroptosis.77 DHODH was recognized as a mitochondrial inhibitor of ferroptosis that reduces ubiquinone to ubiquinol in mitochondria.78 The depletion of DHODH results in excessive lipid peroxidation and ferroptosis in tumor cells.78 High expression of DHODH or GCH1 endows cells with resistance to ferroptosis, while cells with low expression are more vulnerable to ferroptosis. Brequinar, a DHODH inhibitor, can suppress GPX4low tumor growth by inducing ferroptosis. When combined with sulfasalazine treatment, it can induce ferroptosis and suppress GPX4high tumor growth.79,80 Moreover, phospholipase A2 group VI (iPLA2b) can suppress p53-related ferroptosis by trimming oxidized PUFA tails from PLs, and PUFA-OOH alone has no effect on ferroptosis.81 Monounsaturated fatty acids (MUFAs) also show anti-ferroptotic effects in an ACSL3-dependent manner.82
Factors Aggravating Ferroptosis
The accumulation of intracellular iron could trigger ferroptosis, as we have mentioned above. Several factors promote ferroptosis by directly or indirectly inhibiting GPX4, including RAS-selective-lethal-3 (RSL3),83 ML162, ML210 and ferroptosis-inducing-56 (FIN56) and so forth.84,85 FINO2 accelerates ferroptosis by triggering the peroxidation of PUFA-PLs. SCP2 promotes chondrocyte ferroptosis by mediating the transport of cytoplasmic lipid hydroperoxides to mitochondria.86 Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy could control cellular iron levels,87 and overexpression of NCOA4 promoted chondrocyte ferroptosis and aggravated posttraumatic OA.88 Ferric ammonium citrate (FAC), a typical inducer of ferroptosis, could upregulate the expression of MMP-3, MMP-13, and ADAMTS-5 in chondrocytes by increasing intracellular iron and ROS levels.30 Advanced glycation end products (AGEs) promote chondrocyte ferroptosis and OA progression by decreasing GSH expression and increasing intracellular ROS levels.89
Evidence of Ferroptosis in OA
Iron Metabolism in OA
Iron accumulation and dysfunction in iron homeostasis have been observed in OA patients. The iron concentration in the synovial fluid of osteoarthritic joints was markedly higher than that in healthy joints,90 and another study revealed that the iron concentration in synovial fluid has positive correlation with OA severity.32 The iron concentration in synovial fluid was increased in OA patients, but not in rheumatoid arthritis (RA) patients.31 Iron deposition was also found in the osteoarthritic synovium, and more Fe3+, Fe2+ and total iron deposition were found in osteoarthritic cartilage than in normal cartilage.91 Serum ferritin and iron are indicators of the iron store level in total body, and serum ferritin levels were positively correlated with OA severity.92,93 Increased serum ferritin levels were independent of age, sex, C-reactive protein levels, and body mass index.93 Patients with hereditary haemochromatosis, whose body iron content is overloaded, suffer from OA more frequently than healthy individuals.94 The negative effects of iron overload (IO) were shown in an IO model by Jing et al,31 and significant cartilage degeneration and subchondral bone destruction, and higher Osteoarthritis Research Society International (OARSI) scores were observed in the IO group, compared with the control group. In addition, increased a ADAMTS5 and MMP13 expression was found in the IO group, indicating that iron overload contributed greatly to cartilage degeneration.31 Moreover, Wu et al95 proposed that proper iron intake was beneficial for slowing OA development, while both excessive and a lack of iron intake may increase the risk of OA. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been identified as a crucial mechanism for regulating cellular iron levels.87 The JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates OA through ferritinophagy88 (Figure 1).
Lipid Peroxidation in OA
4-HNE and MDA, two markers of oxidative stress and lipid peroxidation, are closely linked to OA development. Increased levels of 4-HNE and MDA were found in osteoarthritic synovial cells compared with normal synovial cells.37 Additionally, higher levels of 4-HNE were found in the osteoarthritic synovial fluids.96 Moreover, MDA and 4-HNE levels in OA cartilage were measured by immunostaining, revealing increased fluorescence intensity in the OA patient groups.97 In animal models, higher levels of 4-HNE were found in the cartilage and synovial fluid of the surgery-induced OA dog model, and intraarticular administration of 4-HNE led to cartilage destruction and increased the expression of MMP13, ADAMTS5, and cyclooxygenase-2 (COX2) in dogs.98 In addition to surgically induced OA models, monosodium iodoacetate (MIA)-induced OA models have also presented the evidence of lipid peroxidation.99,100 These results support the role of lipid peroxidation in contributing to cartilage degeneration and OA development.
Ferric citrate (FAC), a ferroptosis inducer, increased MMP3 and MMP13 levels in chondrocytes, promoted chondrocyte apoptosis,31 induced lipid ROS accumulation, and altered the expression of ferroptosis-related proteins including SLC7A11, GPX4, P53, NRF2-ARE and ACSL4.101 FAC reduced intracellular calcium storage and promoted iron accumulation. Furthermore, FAC reduced the expression of MMP-13 and promoted the expression of FTH1 and FTL.102 Erastin, another typical ferroptosis inducer, increased the expression of MMP13 and decreased the expression of type II collagen. Additionally, ferrostatin-1 (Fer-1) can protect chondrocytes from ferroptosis and ameliorate OA progression in an animal model.101
Changes in Key Ferroptosis Factors in OA
Decreased GPX4 and increased MDA levels were found in ACLT-induced osteoarthritic cartilage103 and in the serum of Freund’s adjuvant-induced OA rats.104 Additionally, reduced GSH levels were found in the cartilage of the medial meniscus resection OA model105, in the plasma of MIA-induced OA rats99,100 and in the serum of OA patients.106
The loss of GPX4 is vital for OA pathogenesis. The expression of GPX4 in OA cartilage was markedly lower than that in undamaged cartilage.32 GPX4 downregulation not only rendered chondrocytes more vulnerable to oxidative stress but also exacerbated cartilage degeneration via the MAPK/NF-κB pathway.32 Moreover, the depletion of GPX4 by AAV-Gpx4 shRNA accelerated OA progression in posttraumatic OA mouse model.32 The same result was obtained by conditional knockout of GPX4 in mouse cartilage in another study.107 These findings indicated that OA development was accompanied by the loss of GPX4, which in turn promoted and exacerbated OA.
OA pathogenesis is closely related to mechanical overload and cartilage abrasion. Piezo1, a Ca2+ channel, is a mechanical sensor in OA that promotes cartilage degeneration and exacerbates OA development.108–111 Therefore, another study investigated the relationship between Piezo1 and ferroptosis and concluded that inhibiting Piezo1 can increase GPX4 expression, alleviate the ferroptosis and attenuate the severity of OA. Further experiments revealed that Piezo1 affected GPX4 expression through Ca2+ influx.107 However, transient receptor potential vanilloid 1 (TRPV1), another ion channel, inhibited ferroptosis by promoting GPX4 expression, and its anti-ferroptotic effect was markedly reduced in the GPX4+/− OA mouse model.112 Liu et al113 proposed that GPX4 was regulated by heat shock protein family A member 5 (HSPA5) and the RNA-binding protein SND1. HSPA5 directly binds to GPX4 and increases GPX4 expression. SND1 promotes GPX4 degradation by binding with HSPA5 at the 3ʹUTR and destabilizing HSPA5 mRNA.113
CoQ10 is another ferroptosis inhibitor that is independent of GPX4. Similar to GPX4, CoQ10 also exerts great potential in ameliorating OA. The administration of CoQ10 can ameliorate OA progression in GPX4-knockout mice.107 CoQ10 alleviated cartilage degradation and pain in the MIA-induced OA rat model by regulating the production of nitric oxide and inflammatory factors, including iNOS, IL-6, IL-1β, IL-15, MMP-13, RAGE and nitrotyrosine.114 CoQ10 encapsulated in micelles slowed MIA-induced OA in rats by inhibiting inflammatory cell death. The inflammatory cell death markers pMLKL, RIP1 and RIP3 were markedly reduced in the synovium after CoQ10-micelle administration.115 Moreover, CoQ10 reduced IL-1β-induced inflammation by interfering with the MAPK signaling in rat chondrocytes.116 These findings suggested a protective role of CoQ10 in OA.
Drugs Targeting Ferroptosis and Lipid Peroxidation in OA Treatment
In recent years, numerous compounds have been reported to be effective in preventing ferroptosis and slowing the progression of OA. Various iron chelators can be used in the treatment of iron overload. Among these, DFP, DFX, and DFO are significant. Each of these chelators has its own set of advantages and disadvantages. DFO, a nontoxic parenteral iron chelator, has been clinically approved and has shown efficacy in long-term iron chelation therapy. DFP, an oral iron chelator, could serve as a viable option for patients who have not responded to DFO or DFX. DFX has fewer gastrointestinal side effects and is more friendly to patients with high gastrointestinal sensitivity.117,118 Patients taking DFP commonly experience gastrointestinal symptoms and agranulocytosis as the most prevalent adverse events.119 Adverse events associated with DFO include growth retardation, skin reactions, ocular and auditory issues, allergic reactions, and bone abnormalities. Moreover, high doses have been linked to the observation of pulmonary and neurological disorders.120 Intraarticular administration of deferoxamine (DFO) or Fer-1 twice per week for eight continuous weeks can attenuate OA development by preventing chondrocyte ferroptosis in ACLT-induced OA mouse models.32 In addition, DFO abrogated the increase in the expression of MMP-13 and MMP-3 induced by interleukin-1beta (IL-1β).31 Another study confirmed that DFO inhibited TNF-α, IL-1β, and type X collagen expression.38 Lactoferrin, a naturally occurring iron chelator, can inhibit IL-1β-induced prostaglandin E2 (PGE2) production and COX2 expression in human osteoarthritic chondrocytes.121
Apart from iron chelators mentioned above, numerous compounds have shown efficacy in treating OA by affecting ferroptosis. Quercetin alleviated mitochondrial dysfunction by upregulating the AMPK/SIRT1 signaling pathway in OA rats.105,122 Cashew nut administration reduced pain-like behavior and reversed cartilage damage in MIA-induced rats. In addition, cashew nuts showed antioxidant effects and could inhibit lipid peroxidation by restoring GSH, catalase and GPX levels.123 Zinc protected chondrosarcoma cells from oxidative stress and slowed MIA-induced OA progression through Nrf2-mediated changes in antioxidants, cytokines and MMP.106 D-mannose can protect chondrocytes by reducing the sensitivity to ferroptosis and preventing OA development.103 The administration of collagen type III restored serum levels of MDA and GSH and ameliorated MIA-induced osteoarthritic radiographic images and histopathological changes in the joints.100 Platelet-rich plasma (PRP) reduced serum lipid peroxides, GSH and glutathione S-transferase (GST) levels in MIA-induced osteoarthritic rats, suppressed joint inflammation and oxidative stress and ameliorated OA progression.124 Astaxanthin retarded OA progression by inhibiting ferroptosis in chondrocytes.125 Biochanin A protected osteoarthritic chondrocytes from iron overload by inhibiting TfR1, promoting FPN and regulating the System xc-/GPX4 axis.126 Theaflavin-3,3ʹ-digallate attenuated erastin-induced chondrocyte ferroptosis by regulating the NRF2/GPX4 pathway in OA.127 Icariin promoted synovial cell survival after lipopolysaccharide (LPS) treatment by inhibiting ferroptosis via enhancing the SLC7A11/GPX4 signaling.39,128 One recent study reported that lipoxin A4 mitigates the progression of knee OA in rats by counteracting ferroptosis through the activation of the ESR2/LPAR3/Nrf2 axis in synovial fibroblast-like synoviocytes.129 Capsiate, a metabolite produced by the gut microbiota, suppressed the expression of HIF-1α and reduced ferroptosis-relative OA progression by activating SLC2A1.130 Cardamonin mitigates chondrocyte inflammation and cartilage degradation in OA by suppressing ferroptosis through the p53 pathway.131 Curcumin counteracts erastin-induced chondrocyte ferroptosis by increasing the expression of Nrf2.132 Baicalein restricts the progression of OA by suppressing ferroptosis in chondrocytes through the AMPK/Nrf2/HO-1 signaling pathway.133 Forkhead box O3 modulates ECM and ameliorates the progression of OA by inhibiting ferroptosis through the inactivation of NF-κB/MAPK signaling.134 P21, an indicator of aging, resists ferroptosis in osteoarthritic chondrocytes by regulating the stability of GPX4. P21 significantly influenced the recruitment of GPX4 to the linear ubiquitin chain assembly complex (LUBAC) and regulated the level of M1-linked ubiquitination of GPX4. P21 knockdown aggravated cartilage degradation in DMM-induced OA mouse models.135 Vitamin K2 attenuates OA by inhibiting ferroptosis and ECM degradation through activating GPX4 and increasing intracellular GSH content.136 Sarsasapogenin reduced chondrocyte ferroptosis and alleviated OA progression through the promotion of YAP1.137,138 Another study showed that quercetin inhibited inflammation and apoptosis in chondrocytes and modulated synovial macrophage polarization to the M2 phenotype.139 Vitamin E acted as an antioxidant and reduced the cartilage matrix degradation induced by H2O2 by inhibiting lipid peroxidation in chondrocytes.36 N-acetyl cysteine (NAC) reversed the H2O2-induced GSH reduction40 and IL-1β mediated enhancement of ADAMTS-5, MMP-3, and MMP-13 expression.140 BAPTA-AM, a calcium chelator, can ameliorate iron overload-induced cartilage degeneration and mitochondrial dysfunction in chondrocytes.30 FAC treatment markedly promoted the expression of MMPs and chondrocyte apoptosis, which could be reversed by BAPTA‑AM. Moreover, BAPTA‑AM suppressed iron influx into chondrocytes and reduced downstream ROS generation and mitochondrial dysfunction.30 The efficacy of reducing Ca2+ influx in countering ferroptosis was also confirmed by knocking out the Ca2+ channel Piezo1.107 Epigallocatechin-3-gallate (EGCG) and selenomethionine (SeMet) can efficiently synthesize polyphenol-based nanodrugs in aqueous media. These EGCG-based nanodrugs effectively reduce GPX4 inactivation, abnormal Fe2+ accumulation, and lipid peroxidation induced by oxidative stress, ultimately attenuating cartilage degradation in DMM-induced OA mouse models141 (Table 1).
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Table 1 Compounds Targets Ferroptosis or Lipid Peroxidation in the Treatment of OA on Animal Models or in vitro Cultured Chondrocytes |
Discussions
Ferroptosis is related to an iron-dependent cell death characterized by chondrocyte dysfunction and lipid peroxidation.142 It has been more than ten years since ferroptosis was first identified by Stockwell’s team, and oxidative stress and lipid peroxidation have long been confirmed in osteoarthritic chondrocytes and synoviocytes. However, in the last two years, the role of lipid peroxidation and ferroptosis has started to be reconsidered and focused on OA. Lipid peroxidation, as shown by MDA levels, and 4-HNE-mediated downregulation of antioxidant system, as shown by GSH and GPX expression levels, establish the relationship between ferroptosis and OA. Changes in osteoarthritic cartilage in iron-overload models and iron accumulation and lipid peroxidation in OA models have been observed, and ferroptosis inhibitors can restore cartilage homeostasis. These findings indicate that ferroptosis is tightly linked to OA.
Two main pathways that control ferroptosis, the System Xc− /cystine/GSH/GPX4 pathway and the FSP1/CoQ10 pathway, are related to OA, and the depletion of GPX4 can accelerate OA progression while supplementation with CoQ10 can relieve OA development. Many related findings support that ferroptosis is a negative biological process in chondrocytes and promotes OA progression. However, there are still some contradictory findings about ferroptosis and lipid peroxidation in OA. One study indicated a significant decrease in GPX4 expression within the cartilage of 55 OA patients compared to undamaged cartilage.32 However, another study reported that GPX expression and its activity increased dose and time-dependently in IL-1β-treated bovine chondrocytes.143 IL-1β result in a transient accumulation of H2O2 within the mitochondria, leading to subsequent damage to the mitochondria. The reason for the different changes in GPX expression in the two studies may be due to the different phases of OA. The acute inflammatory changes induced by IL-1β in chondrocytes may not fully represent the natural pathogenesis of OA, which is chronic cartilage abrasion. IL-1β prompts an elevation in GPX4 expression to combat oxidative stress, potentially serving as a self-protective mechanism for chondrocytes. However, in the chronic and natural process of OA onset, GPX4 content decreases, ultimately contributes to an increase in ferroptosis and cartilage degeneration. Another study showed that intraarticular injection of sulfasalazine, a system Xc− inhibitor, reduced GSH levels in chondrocytes and mitigated cartilage damage and knee swelling in a surgery induced rat OA model.144 Moreover, OA patients exhibited markedly increased activity of glutathione transforming enzymes and all antioxidant enzymes in synovial fluid compared with the control groups.145 The reason for the seemingly contradictory role of ferroptosis in OA pathogenesis is unclear, and different stages of OA may account for these differences. Specifically, in the preliminary OA stage, the elevated expression of antioxidant enzymes in OA patients may be attributed to a response to increased levels of these enzymes. This increase in antioxidants serves as a compensatory mechanism to prevent cartilage destruction. However, in the end stage of OA, these antioxidants may be overwhelmed by large amounts of ROS and oxidative stress.146
Although ferroptosis can lead to chondrocyte loss and death, it is not always a bad thing in OA. That is, the ferroptosis of normal chondrocytes promotes the progression of OA, while the ferroptosis of senescent cells may help alleviate OA. During the early stages of OA, ferroptosis of chondrocytes results in reduced synthesis of the cartilage matrix and increased cartilage degradation. However, in the late stages of OA, the detrimental impact of senescent chondrocytes outweighs the supportive role of cartilage matrix synthesis by normal chondrocytes. During this phase, ferroptosis may act as a senolytic which can eliminate senescent chondrocytes and preventing further progression of OA. Cellular senescence in chondrocytes contributes greatly to OA pathogenesis.16,147–149 Selective elimination of senescent cells in a posttraumatic OA mouse model could ameliorate OA progression,150 while intraarticular injection of senescent fibroblasts induced OA-like changes in mice.151,152 Senescent cells are characterized by cell cycle arrest, resistance to apoptosis and continuous senescence-associated secretory phenotype (SASP) secretion153. Moreover, senescent chondrocytes were reported to be tolerant to ferroptosis in one recent study.154 This resistance to ferroptosis may be attributed to the upregulation of membrane protein excitatory amino acid transporter protein 1 (EAAT1), which increases cellular glutamate levels and activates the glutathione system to resist ferroptosis. The administration of a UCPH-101, a specific inhibitor of EAAT1, or EAAT1-siRNA transfection largely increased the sensitivity of senescent chondrocytes to ferroptosis.154 Intraarticular administration of UCPH-101, eliminated senescent chondrocytes from cartilage, and markedly delayed the progression of OA.154 However, in addition to targeting senescence by inducing ferroptosis, ferroptosis inhibitors can also be effective in eliminating senescence. For example, quercetin can inhibit ferroptosis as mentioned previously. In fact, quercetin was one of the first discovered senolytics which is a group of drugs that selectively eliminate senescent cells.147,155 Certainly, clearing senescent chondrocytes by selectively inducing ferroptosis in these cells is effective, whereas chondrocytes ferroptosis is collectively detrimental to OA pathogenesis.
There are also limitations of the current research on ferroptosis in OA. These studies mainly focused on chondrocyte ferroptosis but ignored other tissues in osteoarthritic joints, such as the synovium, infrapatellar fat pad and subchondral bone. As a highly heterogeneous cartilage degenerative disease, the etiology of OA can be very complicated.156 Although chondrocytes are the predominant cells in cartilage, other tissues and cells also affect cartilage degeneration.8 For example, regulated fibroblast growth factor (FGF) signaling is a vital for the homeostasis of cartilage, and abnormal FGF signaling contributes to the development of OA.157 Osteoblast dysregulation also plays an important role in OA pathogenesis.158 Senescent fibroblast-like synoviocytes greatly contribute to the inflammatory environment of the joint and can promote chondrocyte senescence by secreting SASP factors.159 Moreover, synovial inflammation significantly contributes to OA pathogenesis, and the degree of synovitis is related to OA severity.160,161 Macrophages are the main cells that contribute to synovial inflammatory environment, exacerbating OA and accelerating joint degeneration. M1 macrophages exert proinflammatory effects, while M2 macrophages exert anti-inflammatory effects.162 This evidence indicates the role of other tissues and cells in the joint in regulating OA pathogenesis. Increased levels of 4-HNE and MDA were observed in osteoarthritic synovial cells and synovial fluid, suggesting that lipid peroxidation occurred in these tissues and cells apart from chondrocytes. Whether lipid peroxidation and ferroptosis in these cells affect OA pathogenesis remains unclear, and whether there is any crosstalk between these cells and chondrocytes further study. Future research should evaluate the role of ferroptosis in the entire joint cavity environment, especially synovial cells and macrophages, to determine how it affects their metabolites and the interactions between cells, ultimately impacting the progression of OA. Additionally, conducting more comprehensive and detailed animal experiments, especially large animal experiments such as those involving dogs and monkeys, would be beneficial for evaluating the therapeutic effects and potential side effects of ferroptosis regulators in the treatment of OA.
Conclusions
The role of ferroptosis and lipid peroxidation in OA pathogenesis and development has gradually aroused the interest of researchers in recent years. Several drugs targeting ferroptosis have achieved preliminary progress in OA animal models. However, there is still a long way to go before we clearly understand how ferroptosis works and its regulation in osteoarthritic chondrocytes. In conclusion, targeting ferroptosis shows potential in the prevention and treatment of OA.
Abbreviations
OA, Osteoarthritis; ECM, extracellular matrix; GPX4, Glutathione peroxidase 4; DMT1, divalent metal-ion transporter 1; FPN, ferroportin; Tf, transferrin; TfR1, transferrin receptor 1; FTL, ferritin light chain; FTH1, ferritin heavy chain 1; ROS, reactive oxygen species; PUFA, Polyunsaturated fatty acid; ACSL1, acyl-CoA synthetase long-chain family member 1; LPCAT3, lysophosphatidylcholine acyltransferase 3; PL, phospholipid; ALOXs, lipoxygenases; PEBP1, phosphatidylethanolamine binding protein 1; POR, phosphatidylethanolamine binding protein 1; MDA, malondialdehyde; 4-HNE, 4-hydroxynonenal; ER, endoplasmic reticulum; GSH, glutathione; SLC7A11, solute carrier family 7 member 11; RSL3, RAS-selective-lethal-3; FIN56, Ferroptosis-Inducer-56; FSP1, ferroptosis suppressor protein 1; CoQ10, Coenzyme Q10; DHODH, dihydroorotate dehydrogenase; GCH1, GTP cyclohydrolase 1; BH4, tetrahydrobiopterin; NADPH, nicotinamide adenine dinucleotide phosphate; IL4i1, interleukin-4-induced-1; In3Py, indole-3-pyruvate; iPLA2b, phospholipase A2 group VI; MUFA, Monounsaturated fatty acid; RA, rheumatoid arthritis; OARSI, Osteoarthritis Research Society International; ADAMTS5, a disintegrin and metalloproteinase with thrombospondin 5; MMP13, matrix metalloproteinase-13; COX2, cyclooxygenase-2; MIA, monosodium iodoacetate; FAC, Ferric citrate; Fer-1, ferrostatin-1; TRPV1, transient receptor potential vanilloid 1; HSPA5, heat shock protein family A member 5; DFO, deferoxamine; IL-1β, interleukin-1beta; PGE2, prostaglandin E2; PRP, platelet-rich plasma; GST, glutathione S-transferase; LPS, lipopolysaccharide; NAC, N-acetyl cysteine; SASP, Senescence-associated secretory phenotype; EAAT1, excitatory amino acid transporter protein 1; FGF, fibroblast growth factor.
Data Sharing Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Acknowledgments
This manuscript was polished by Springer Nature author service.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
This work was supported by the National Natural Science Foundation of China (NO. 81672197).
Disclosure
The authors declare no conflicts of interest in this work.
References
1. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393(10182):1745–1759. doi:10.1016/S0140-6736(19)30417-9
2. Mandl LA. Osteoarthritis year in review 2018: clinical. Osteoarthritis Cartilage. 2019;27(3):359–364. doi:10.1016/j.joca.2018.11.001
3. Michael JW, Schluter-Brust KU, Eysel P. The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee. Dtsch Arztebl Int. 2010;107(9):152–162. doi:10.3238/arztebl.2010.0152
4. Favero M, Belluzzi E, Ortolan A, et al. Erosive hand osteoarthritis: latest findings and outlook. Nat Rev Rheumatol. 2022;18(3):171–183. doi:10.1038/s41584-021-00747-3
5. McAlindon TE, Hunnicutt JL, Roberts MB, et al. Associations of inflammatory and metabolic biomarkers with incident erosive hand osteoarthritis in the osteoarthritis initiative cohort. Osteoarthritis Cartilage. 2024;32(5):592–600. doi:10.1016/j.joca.2023.10.011
6. Silvestre MP, Rodrigues AM, Canhao H, et al. Cross-talk between diet-associated dysbiosis and hand osteoarthritis. Nutrients. 2020;12(11):3469. doi:10.3390/nu12113469
7. Li H, Jiang X, Xiao Y, et al. Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways. Bone Res. 2023;11(1):58. doi:10.1038/s41413-023-00292-7
8. Rahmati M, Nalesso G, Mobasheri A, Mozafari M. Aging and osteoarthritis: central role of the extracellular matrix. Ageing Res Rev. 2017;40:20–30. doi:10.1016/j.arr.2017.07.004
9. Lu H, Jia C, Wu D, et al. Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway. Cell Death Dis. 2021;12(10):865. doi:10.1038/s41419-021-04157-x
10. Musumeci G, Castrogiovanni P, Trovato FM, et al. Biomarkers of chondrocyte apoptosis and autophagy in osteoarthritis. Int J Mol Sci. 2015;16(9):20560–20575. doi:10.3390/ijms160920560
11. Tian F, Wang J, Zhang Z, Yang J. LncRNA SNHG7/miR-34a-5p/SYVN1 axis plays a vital role in proliferation, apoptosis and autophagy in osteoarthritis. Biol Res. 2020;53(1):9. doi:10.1186/s40659-020-00275-6
12. Huang R, Hui Z, Wei S, et al. IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis. J Cell Physiol. 2022;237(1):118–127. doi:10.1002/jcp.30537
13. Coryell PR, Diekman BO, Loeser RF. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat Rev Rheumatol. 2021;17(1):47–57. doi:10.1038/s41584-020-00533-7
14. Liu Y, Zhang Z, Li T, Xu H, Zhang H. Senescence in osteoarthritis: from mechanism to potential treatment. Arthritis Res Ther. 2022;24(1):174. doi:10.1186/s13075-022-02859-x
15. Xie J, Wang Y, Lu L, Liu L, Yu X, Pei F. Cellular senescence in knee osteoarthritis: molecular mechanisms and therapeutic implications. Ageing Res Rev. 2021;70:101413. doi:10.1016/j.arr.2021.101413
16. Rim YA, Nam Y, Ju JH. The role of chondrocyte hypertrophy and senescence in osteoarthritis initiation and progression. Int J Mol Sci. 2020;21(7):2358. doi:10.3390/ijms21072358
17. Park S, Bello A, Arai Y, et al. Functional duality of chondrocyte hypertrophy and biomedical application trends in osteoarthritis. Pharmaceutics. 2021;13(8):1139. doi:10.3390/pharmaceutics13081139
18. Tong W, Zeng Y, Chow DHK, et al. Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade. Ann Rheum Dis. 2019;78(4):551–561. doi:10.1136/annrheumdis-2018-214200
19. An S, Hu H, Li Y, Hu Y. Pyroptosis plays a role in osteoarthritis. Aging Dis. 2020;11(5):1146–1157. doi:10.14336/AD.2019.1127
20. Zhang L, Qiu J, Shi J, Liu S, Zou H. MicroRNA-140-5p represses chondrocyte pyroptosis and relieves cartilage injury in osteoarthritis by inhibiting cathepsin B/Nod-like receptor protein 3. Bioengineered. 2021;12(2):9949–9964. doi:10.1080/21655979.2021.1985342
21. Hu J, Zhou J, Wu J, et al. Loganin ameliorates cartilage degeneration and osteoarthritis development in an osteoarthritis mouse model through inhibition of NF-kappaB activity and pyroptosis in chondrocytes. J Ethnopharmacol. 2020;247:112261. doi:10.1016/j.jep.2019.112261
22. Zheng L, Zhang Z, Sheng P, Mobasheri A. The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis. Ageing Res Rev. 2021;66:101249. doi:10.1016/j.arr.2020.101249
23. Messina OD, Vidal Wilman M, Vidal Neira LF. Nutrition, osteoarthritis and cartilage metabolism. Aging Clin Exp Res. 2019;31(6):807–813. doi:10.1007/s40520-019-01191-w
24. Maeda K, Kobayashi Y, Koide M, et al. The regulation of bone metabolism and disorders by Wnt signaling. Int J Mol Sci. 2019;20(22):5525. doi:10.3390/ijms20225525
25. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. doi:10.1016/j.cell.2012.03.042
26. Battaglia AM, Chirillo R, Aversa I, Sacco A, Costanzo F, Biamonte F. Ferroptosis and cancer: mitochondria meet the “Iron Maiden” cell death. Cells. 2020;9(6):1505. doi:10.3390/cells9061505
27. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381–396. doi:10.1038/s41568-022-00459-0
28. Li J, Jia YC, Ding YX, Bai J, Cao F, Li F. The crosstalk between ferroptosis and mitochondrial dynamic regulatory networks. Int J Biol Sci. 2023;19(9):2756–2771. doi:10.7150/ijbs.83348
29. Stockwell BR. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185(14):2401–2421. doi:10.1016/j.cell.2022.06.003
30. Jing X, Wang Q, Du T, et al.. Calcium chelator BAPTA‑AM protects against iron overload‑induced chondrocyte mitochondrial dysfunction and cartilage degeneration. Int J Mol Med. 2021;48(4). doi:10.3892/ijmm.2021.5029
31. Jing X, Lin J, Du T, et al. Iron overload is associated with accelerated progression of osteoarthritis: the role of DMT1 mediated iron homeostasis. Front Cell Dev Biol. 2020;8:594509. doi:10.3389/fcell.2020.594509
32. Miao Y, Chen Y, Xue F, et al. Contribution of ferroptosis and GPX4’s dual functions to osteoarthritis progression. EBioMedicine. 2022;76:103847. doi:10.1016/j.ebiom.2022.103847
33. Liu J, Kang R, Tang D. Signaling pathways and defense mechanisms of ferroptosis. FEBS J. 2022;289(22):7038–7050. doi:10.1111/febs.16059
34. Goranov NV. Serum markers of lipid peroxidation, antioxidant enzymatic defense, and collagen degradation in an experimental (Pond-Nuki) canine model of osteoarthritis. Vet Clin Pathol. 2007;36(2):192–195. doi:10.1111/j.1939-165X.2007.tb00208.x
35. Sutipornpalangkul W, Morales NP, Charoencholvanich K, Harnroongroj T. Lipid peroxidation, glutathione, vitamin E, and antioxidant enzymes in synovial fluid from patients with osteoarthritis. Int J Rheum Dis. 2009;12(4):324–328. doi:10.1111/j.1756-185X.2009.01430.x
36. Tiku ML, Shah R, Allison GT. Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation. Possible role in cartilage aging and the pathogenesis of osteoarthritis. J Biol Chem. 2000;275(26):20069–20076. doi:10.1074/jbc.M907604199
37. Grigolo B, Roseti L, Fiorini M, Facchini A. Enhanced lipid peroxidation in synoviocytes from patients with osteoarthritis. J Rheumatol. 2003;30(2):345–347.
38. Tchetina EV, Markova GA, Poole AR, et al. Deferoxamine suppresses collagen cleavage and protease, cytokine, and COL10A1 expression and upregulates AMPK and Krebs cycle genes in human osteoarthritic cartilage. Int J Rheumatol. 2016;2016:6432867. doi:10.1155/2016/6432867
39. Luo H, Zhang R. Icariin enhances cell survival in lipopolysaccharide-induced synoviocytes by suppressing ferroptosis via the Xc-/GPX4 axis. Exp Ther Med. 2021;21(1):72. doi:10.3892/etm.2020.9504
40. Dycus DL, Au AY, Grzanna MW, Wardlaw JL, Frondoza CG. Modulation of inflammation and oxidative stress in canine chondrocytes. Am J Vet Res. 2013;74(7):983–989. doi:10.2460/ajvr.74.7.983
41. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest. 2005;115(5):1258–1266. doi:10.1172/JCI24356
42. Anderson GJ, Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr. 2017;106(Suppl 6):1559S–1566S. doi:10.3945/ajcn.117.155804
43. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403(6771):776–781. doi:10.1038/35001596
44. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet. 1999;21(2):195–199. doi:10.1038/5979
45. Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37(11):1264–1269. doi:10.1038/ng1658
46. Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002;99(10):3505–3516. doi:10.1182/blood.V99.10.3505
47. Adameyko KI, Burakov AV, Finoshin AD, et al. Conservative and atypical ferritins of sponges. Int J Mol Sci. 2021;22(16):8635. doi:10.3390/ijms22168635
48. Ajoolabady A, Aslkhodapasandhokmabad H, Libby P, et al. Ferritinophagy and ferroptosis in the management of metabolic diseases. Trends Endocrinol Metab. 2021;32(7):444–462. doi:10.1016/j.tem.2021.04.010
49. Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014;509(7498):105–109. doi:10.1038/nature13148
50. Andrews NC. Probing the iron pool. Focus on “Detection of intracellular iron by its regulatory effect”. Am J Physiol Cell Physiol. 2004;287(6):C1537–1538. doi:10.1152/ajpcell.00435.2004
51. Cairo G, Recalcati S. Iron-regulatory proteins: molecular biology and pathophysiological implications. Expert Rev Mol Med. 2007;9(33):1–13. doi:10.1017/S1462399407000531
52. Rauen U, Springer A, Weisheit D, et al. Assessment of chelatable mitochondrial iron by using mitochondrion-selective fluorescent iron indicators with different iron-binding affinities. Chembiochem. 2007;8(3):341–352. doi:10.1002/cbic.200600311
53. Lv H, Shang P. The significance, trafficking and determination of labile iron in cytosol, mitochondria and lysosomes. Metallomics. 2018;10(7):899–916. doi:10.1039/C8MT00048D
54. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94(3):909–950. doi:10.1152/physrev.00026.2013
55. Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369–379. doi:10.1038/cdd.2015.158
56. Ayala A, Munoz MF, Arguelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438. doi:10.1155/2014/360438
57. Tsikas D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges. Anal Biochem. 2017;524:13–30. doi:10.1016/j.ab.2016.10.021
58. Yang H, Hu Y, Weng M, et al. Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer. J Adv Res. 2022;37:91–106. doi:10.1016/j.jare.2021.10.001
59. Park MW, Cha HW, Kim J, et al. NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases. Redox Biol. 2021;41:101947. doi:10.1016/j.redox.2021.101947
60. Li N, Wang W, Zhou H, et al. Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury. Free Radic Biol Med. 2020;160:303–318. doi:10.1016/j.freeradbiomed.2020.08.009
61. Chen C, Wang D, Yu Y, et al. Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI. Cell Death Dis. 2021;12(1):65. doi:10.1038/s41419-020-03362-4
62. Liu P, Feng Y, Li H, et al. Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis. Cell Mol Biol Lett. 2020;25:10. doi:10.1186/s11658-020-00205-0
63. Chng CP, Sadovsky Y, Hsia KJ, Huang C. Site-specific peroxidation modulates lipid bilayer mechanics. Extreme Mech Lett. 2021;42:101148.
64. Barrera G, Gentile F, Pizzimenti S, et al. Mitochondrial dysfunction in cancer and neurodegenerative diseases: spotlight on fatty acid oxidation and lipoperoxidation products. Antioxidants. 2016;5(1):7. doi:10.3390/antiox5010007
65. Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab. 2020;32(6):920–937. doi:10.1016/j.cmet.2020.10.011
66. Bridges RJ, Natale NR, Patel SA. System xc(-) cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 2012;165(1):20–34. doi:10.1111/j.1476-5381.2011.01480.x
67. Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A. 2016;113(34):E4966–4975. doi:10.1073/pnas.1603244113
68. Seiler A, Schneider M, Forster H, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8(3):237–248. doi:10.1016/j.cmet.2008.07.005
69. Banjac A, Perisic T, Sato H, et al. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene. 2008;27(11):1618–1628. doi:10.1038/sj.onc.1210796
70. Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:101107. doi:10.1016/j.redox.2019.101107
71. Anandhan A, Dodson M, Shakya A, et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci Adv. 2023;9(5):eade9585. doi:10.1126/sciadv.ade9585
72. Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–692. doi:10.1038/s41586-019-1705-2
73. Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–698. doi:10.1038/s41586-019-1707-0
74. Nakamura T, Hipp C, Santos Dias Mourao A, et al. Phase separation of FSP1 promotes ferroptosis. Nature. 2023;619(7969):371–377.
75. Zeitler L, Fiore A, Meyer C, et al. Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism. Elife. 2021;10:e64806.
76. Soula M, Weber RA, Zilka O, et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol. 2020;16(12):1351–1360. doi:10.1038/s41589-020-0613-y
77. Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci. 2020;6(1):41–53. doi:10.1021/acscentsci.9b01063
78. Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593(7860):586–590. doi:10.1038/s41586-021-03539-7
79. Natale R, Wheeler R, Moore M, et al. Multicenter phase II trial of brequinar sodium in patients with advanced melanoma. Ann Oncol. 1992;3(8):659–660. doi:10.1093/oxfordjournals.annonc.a058298
80. Peters GJ, Schwartsmann G, Nadal JC, et al. In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. Cancer Res. 1990;50(15):4644–4649.
81. Chen D, Chu B, Yang X, et al. iPLA2beta-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat Commun. 2021;12(1):3644. doi:10.1038/s41467-021-23902-6
82. Magtanong L, Ko PJ, To M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol. 2019;26(3):420–432e429. doi:10.1016/j.chembiol.2018.11.016
83. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15(3):234–245. doi:10.1016/j.chembiol.2008.02.010
84. Dixon SJ, Winter GE, Musavi LS, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10(7):1604–1609. doi:10.1021/acschembio.5b00245
85. Shimada K, Skouta R, Kaplan A, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12(7):497–503. doi:10.1038/nchembio.2079
86. Dai T, Xue X, Huang J, et al. SCP2 mediates the transport of lipid hydroperoxides to mitochondria in chondrocyte ferroptosis. Cell Death Discov. 2023;9(1):234. doi:10.1038/s41420-023-01522-x
87. Wu H, Liu Q, Shan X, Gao W, Chen Q. ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4. Autophagy. 2023;19(7):2062–2077. doi:10.1080/15548627.2023.2170960
88. Sun K, Hou L, Guo Z, et al. JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy. Free Radic Biol Med. 2023;200:87–101. doi:10.1016/j.freeradbiomed.2023.03.008
89. Suzuki A, Yabu A, Nakamura H. Advanced glycation end products in musculoskeletal system and disorders. Methods. 2022;203:179–186. doi:10.1016/j.ymeth.2020.09.012
90. Yazar M, Sarban S, Kocyigit A, Isikan UE. Synovial fluid and plasma selenium, copper, zinc, and iron concentrations in patients with rheumatoid arthritis and osteoarthritis. Biol Trace Elem Res. 2005;106(2):123–132. doi:10.1385/BTER:106:2:123
91. Ogilvie-Harris DJ, Fornaiser VL. Synovial iron deposition in osteoarthritis and rheumatoid arthritis. J Rheumatol. 1980;7(1):30–36.
92. Kennish L, Attur M, Oh C, et al. Age-dependent ferritin elevations and HFE C282Y mutation as risk factors for symptomatic knee osteoarthritis in males: a longitudinal cohort study. BMC Musculoskelet Disord. 2014;15:8. doi:10.1186/1471-2474-15-8
93. Nugzar O, Zandman-Goddard G, Oz H, Lakstein D, Feldbrin Z, Shargorodsky M. The role of ferritin and adiponectin as predictors of cartilage damage assessed by arthroscopy in patients with symptomatic knee osteoarthritis. Best Pract Res Clin Rheumatol. 2018;32(5):662–668. doi:10.1016/j.berh.2019.04.004
94. Van Vulpen LF, Roosendaal G, van Asbeck BS, Mastbergen SC, Lafeber FP, Schutgens RE. The detrimental effects of iron on the joint: a comparison between haemochromatosis and haemophilia. J Clin Pathol. 2015;68(8):592–600. doi:10.1136/jclinpath-2015-202967
95. Wu L, Si H, Zeng Y, et al. Association between iron intake and progression of knee osteoarthritis. Nutrients. 2022;14(8):1674.
96. Morquette B, Shi Q, Lavigne P, Ranger P, Fernandes JC, Benderdour M. Production of lipid peroxidation products in osteoarthritic tissues: new evidence linking 4-hydroxynonenal to cartilage degradation. Arthritis Rheum. 2006;54(1):271–281. doi:10.1002/art.21559
97. Shah R, Raska K, Tiku ML. The presence of molecular markers of in vivo lipid peroxidation in osteoarthritic cartilage: a pathogenic role in osteoarthritis. Arthritis Rheum. 2005;52(9):2799–2807. doi:10.1002/art.21239
98. Shi Q, Abusarah J, Zaouter C, et al. New evidence implicating 4-hydroxynonenal in the pathogenesis of osteoarthritis in vivo. Arthritis Rheumatol. 2014;66(9):2461–2471. doi:10.1002/art.38704
99. Pathak NN, Balaganur V, Lingaraju MC, et al. Effect of atorvastatin, a HMG-CoA reductase inhibitor in monosodium iodoacetate-induced osteoarthritic pain: implication for osteoarthritis therapy. Pharmacol Rep. 2015;67(3):513–519. doi:10.1016/j.pharep.2014.12.005
100. Abdel jaleel GA, Saleh DO, Al-Awdan SW, Hassan A, Asaad GF. Impact of type III collagen on monosodium iodoacetate-induced osteoarthritis in rats. Heliyon. 2020;6(6):e04083. doi:10.1016/j.heliyon.2020.e04083
101. Yao X, Sun K, Yu S, et al. Chondrocyte ferroptosis contribute to the progression of osteoarthritis. J Orthop Translat. 2021;27:33–43. doi:10.1016/j.jot.2020.09.006
102. Ohno T, Hashimoto N, Mitsui K, Nishimura H, Hagiwara H. Iron overload inhibits calcification and differentiation of ATDC5 cells. J Biochem. 2012;151(1):109–114. doi:10.1093/jb/mvr124
103. Zhou X, Zheng Y, Sun W, et al. D-mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF-2alpha-dependent manner. Cell Prolif. 2021;54(11):e13134. doi:10.1111/cpr.13134
104. Ma D, He J, He D. Chamazulene reverses osteoarthritic inflammation through regulation of matrix metalloproteinases (MMPs) and NF-kbeta pathway in in-vitro and in-vivo models. Biosci Biotechnol Biochem. 2020;84(2):402–410. doi:10.1080/09168451.2019.1682511
105. Qiu L, Luo Y, Chen X. Quercetin attenuates mitochondrial dysfunction and biogenesis via upregulated AMPK/SIRT1 signaling pathway in OA rats. Biomed Pharmacother. 2018;103:1585–1591. doi:10.1016/j.biopha.2018.05.003
106. Huang TC, Chang WT, Hu YC, et al. Zinc protects articular chondrocytes through changes in Nrf2-mediated antioxidants, cytokines and matrix metalloproteinases. Nutrients. 2018;10(4):471. doi:10.3390/nu10040471
107. Wang S, Li W, Zhang P, et al. Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx. J Adv Res. 2022;41:63–75. doi:10.1016/j.jare.2022.01.004
108. Lee W, Nims RJ, Savadipour A, et al.. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc Natl Acad Sci U S A. 2021;118(13). doi:10.1073/pnas.2001611118
109. Gao W, Hasan H, Anderson DE, Lee W. The role of mechanically-activated ion channels Piezo1, Piezo2, and TRPV4 in chondrocyte mechanotransduction and mechano-therapeutics for osteoarthritis. Front Cell Dev Biol. 2022;10:885224. doi:10.3389/fcell.2022.885224
110. Lee W, Leddy HA, Chen Y, et al. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc Natl Acad Sci U S A. 2014;111(47):E5114–5122. doi:10.1073/pnas.1414298111
111. Han S. Osteoarthritis year in review 2022: biology. Osteoarthritis Cartilage. 2022;30(12):1575–1582. doi:10.1016/j.joca.2022.09.003
112. Lv Z, Han J, Li J, et al. Single cell RNA-seq analysis identifies ferroptotic chondrocyte cluster and reveals TRPV1 as an anti-ferroptotic target in osteoarthritis. EBioMedicine. 2022;84:104258. doi:10.1016/j.ebiom.2022.104258
113. Lv M, Cai Y, Hou W, et al. The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes. Inflamm Res. 2022;71(4):461–472. doi:10.1007/s00011-022-01547-5
114. Lee J, Hong YS, Jeong JH, et al. Coenzyme Q10 ameliorates pain and cartilage degradation in a rat model of osteoarthritis by regulating nitric oxide and inflammatory cytokines. PLoS One. 2013;8(7):e69362. doi:10.1371/journal.pone.0069362
115. Na HS, Woo JS, Kim JH, et al. Coenzyme Q10 encapsulated in micelles ameliorates osteoarthritis by inhibiting inflammatory cell death. PLoS One. 2022;17(6):e0270351. doi:10.1371/journal.pone.0270351
116. Li X, Guo Y, Huang S, et al. Coenzyme Q10 prevents the Interleukin-1 beta induced inflammatory response via inhibition of MAPK signaling pathways in rat articular chondrocytes. Drug Dev Res. 2017;78(8):403–410. doi:10.1002/ddr.21412
117. Gomber S, Jain P, Sharma S, Narang M. Comparative efficacy and safety of oral iron chelators and their novel combination in children with thalassemia. Indian Pediatr. 2016;53(3):207–210. doi:10.1007/s13312-016-0821-4
118. Mobarra N, Shanaki M, Ehteram H, et al. A review on iron chelators in treatment of iron overload syndromes. Int J Hematol Oncol Stem Cell Res. 2016;10(4):239–247.
119. Hider RC, Hoffbrand AV. The role of deferiprone in iron chelation. N Engl J Med. 2018;379(22):2140–2150. doi:10.1056/NEJMra1800219
120. Poggiali E, Cassinerio E, Zanaboni L, Cappellini MD. An update on iron chelation therapy. Blood Transfus. 2012;10(4):411–422. doi:10.2450/2012.0008-12
121. Rasheed N, Alghasham A, Rasheed Z. Lactoferrin from Camelus dromedarius inhibits nuclear transcription factor-kappa B activation, Cyclooxygenase-2 expression and prostaglandin E2 production in stimulated human chondrocytes. Pharmacogn Res. 2016;8(2):135–141. doi:10.4103/0974-8490.175612
122. Wang Y, Quan F, Cao Q, et al. Quercetin alleviates acute kidney injury by inhibiting ferroptosis. J Adv Res. 2021;28:231–243. doi:10.1016/j.jare.2020.07.007
123. Fusco R, Siracusa R, Peritore AF, et al. The role of cashew (Anacardium occidentale L.) nuts on an experimental model of painful degenerative joint disease. Antioxidants. 2020;9(6):511. doi:10.3390/antiox9060511
124. Ragab GH, Halfaya FM, Ahmed OM, et al. Platelet-rich plasma ameliorates monosodium iodoacetate-induced ankle osteoarthritis in the rat model via suppression of inflammation and oxidative stress. Evid Based Complement Alternat Med. 2021;2021:6692432. doi:10.1155/2021/6692432
125. Wang X, Liu Z, Peng P, Gong Z, Huang J, Peng H. Astaxanthin attenuates osteoarthritis progression via inhibiting ferroptosis and regulating mitochondrial function in chondrocytes. Chem Biol Interact. 2022;366:110148. doi:10.1016/j.cbi.2022.110148
126. He Q, Yang J, Pan Z, et al. Biochanin A protects against iron overload associated knee osteoarthritis via regulating iron levels and NRF2/System xc-/GPX4 axis. Biomed Pharmacother. 2023;157:113915. doi:10.1016/j.biopha.2022.113915
127. Xu C, Ni S, Xu N, et al. Theaflavin-3,3ʹ-digallate inhibits erastin-induced chondrocytes ferroptosis via the Nrf2/GPX4 signaling pathway in osteoarthritis. Oxid Med Cell Longev. 2022;2022:3531995. doi:10.1155/2022/3531995
128. Xiao J, Luo C, Li A, et al. Icariin inhibits chondrocyte ferroptosis and alleviates osteoarthritis by enhancing the SLC7A11/GPX4 signaling. Int Immunopharmacol. 2024;133:112010. doi:10.1016/j.intimp.2024.112010
129. Hu Z, Chen L, Zhao J, et al. Lipoxin A(4) ameliorates knee osteoarthritis progression in rats by antagonizing ferroptosis through activation of the ESR2/LPAR3/Nrf2 axis in synovial fibroblast-like synoviocytes. Redox Biol. 2024;73:103143. doi:10.1016/j.redox.2024.103143
130. Guan Z, Jin X, Guan Z, Liu S, Tao K, Luo L. The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF-1alpha to inhibit knee osteoarthritis-induced ferroptosis. Aging Cell. 2023;22(6):e13807. doi:10.1111/acel.13807
131. Gong Z, Wang Y, Li L, Li X, Qiu B, Hu Y. Cardamonin alleviates chondrocytes inflammation and cartilage degradation of osteoarthritis by inhibiting ferroptosis via p53 pathway. Food Chem Toxicol. 2023;174:113644. doi:10.1016/j.fct.2023.113644
132. Zhou Y, Jia Z, Wang J, et al. Curcumin reverses erastin-induced chondrocyte ferroptosis by upregulating Nrf2. Heliyon. 2023;9(10):e20163. doi:10.1016/j.heliyon.2023.e20163
133. Wan Y, Shen K, Yu H, Fan W. Baicalein limits osteoarthritis development by inhibiting chondrocyte ferroptosis. Free Radic Biol Med. 2023;196:108–120. doi:10.1016/j.freeradbiomed.2023.01.006
134. Zhao C, Sun G, Li Y, et al. Forkhead box O3 attenuates osteoarthritis by suppressing ferroptosis through inactivation of NF-kappaB/MAPK signaling. J Orthop Translat. 2023;39:147–162. doi:10.1016/j.jot.2023.02.005
135. Zheng Z, Shang X, Sun K, et al. P21 resists ferroptosis in osteoarthritic chondrocytes by regulating GPX4 protein stability. Free Radic Biol Med. 2024;212:336–348. doi:10.1016/j.freeradbiomed.2023.12.047
136. He Q, Lin Y, Chen B, et al. Vitamin K2 ameliorates osteoarthritis by suppressing ferroptosis and extracellular matrix degradation through activation GPX4’s dual functions. Biomed Pharmacother. 2024;175:116697. doi:10.1016/j.biopha.2024.116697
137. Chen R, Ying C, Zou Y, et al. Sarsasapogenin inhibits YAP1-dependent chondrocyte ferroptosis to alleviate osteoarthritis. Biomed Pharmacother. 2023;168:115772. doi:10.1016/j.biopha.2023.115772
138. Feng K, Chen Z, Pengcheng L, Zhang S, Wang X. Quercetin attenuates oxidative stress-induced apoptosis via SIRT1/AMPK-mediated inhibition of ER stress in rat chondrocytes and prevents the progression of osteoarthritis in a rat model. J Cell Physiol. 2019;234(10):18192–18205. doi:10.1002/jcp.28452
139. Hu Y, Gui Z, Zhou Y, Xia L, Lin K, Xu Y. Quercetin alleviates rat osteoarthritis by inhibiting inflammation and apoptosis of chondrocytes, modulating synovial macrophages polarization to M2 macrophages. Free Radic Biol Med. 2019;145:146–160. doi:10.1016/j.freeradbiomed.2019.09.024
140. Jing X, Du T, Li T, et al. The detrimental effect of iron on OA chondrocytes: importance of pro-inflammatory cytokines induced iron influx and oxidative stress. J Cell Mol Med. 2021;25(12):5671–5680. doi:10.1111/jcmm.16581
141. Yu H, Song Z, Yu J, et al. Supramolecular self-assembly of EGCG-selenomethionine nanodrug for treating osteoarthritis. Bioact Mater. 2024;32:164–176. doi:10.1016/j.bioactmat.2023.09.020
142. Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31(2):107–125. doi:10.1038/s41422-020-00441-1
143. Mathy-Hartert M, Hogge L, Sanchez C, Deby-DuPont G, Crielaard JM, Henrotin Y. Interleukin-1beta and interleukin-6 disturb the antioxidant enzyme system in bovine chondrocytes: a possible explanation for oxidative stress generation. Osteoarthritis Cartilage. 2008;16(7):756–763. doi:10.1016/j.joca.2007.10.009
144. Tsai WY, Tsai RY, Liu CC, Wu JL, Wong CS. Sulfasalazine attenuates ACL transection and medial menisectomy-induced cartilage destruction by inhibition of cystine/glutamate antiporter. J Orthop Res. 2016;34(4):650–657. doi:10.1002/jor.23069
145. Ostalowska A, Birkner E, Wiecha M, et al. Lipid peroxidation and antioxidant enzymes in synovial fluid of patients with primary and secondary osteoarthritis of the knee joint. Osteoarthritis Cartilage. 2006;14(2):139–145. doi:10.1016/j.joca.2005.08.009
146. Ansari MY, Ahmad N, Haqqi TM. Oxidative stress and inflammation in osteoarthritis pathogenesis: role of polyphenols. Biomed Pharmacother. 2020;129:110452. doi:10.1016/j.biopha.2020.110452
147. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518–536. doi:10.1111/joim.13141
148. Lagoumtzi SM, Chondrogianni N. Senolytics and senomorphics: natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic Biol Med. 2021;171:169–190. doi:10.1016/j.freeradbiomed.2021.05.003
149. Zhang XX, He SH, Liang X, Li W, Li TF, Li DF. Aging, cell senescence, the pathogenesis and targeted therapies of osteoarthritis. Front Pharmacol. 2021;12:728100. doi:10.3389/fphar.2021.728100
150. Jeon OH, Kim C, Laberge RM, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23(6):775–781. doi:10.1038/nm.4324
151. Xu M, Bradley EW, Weivoda MM, et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol a Biol Sci Med Sci. 2017;72(6):780–785. doi:10.1093/gerona/glw154
152. Platas J, Guillen MI, Perez Del Caz MD, et al. Paracrine effects of human adipose-derived mesenchymal stem cells in inflammatory stress-induced senescence features of osteoarthritic chondrocytes. Aging. 2016;8(8):1703–1717. doi:10.18632/aging.101007
153. Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017;16(10):718–735. doi:10.1038/nrd.2017.116
154. Wen Z, Xia G, Liang C, et al. Selective clearance of senescent chondrocytes in osteoarthritis by targeting EAAT1 to induce ferroptosis. Antioxid Redox Signal. 2023;39:262–277. doi:10.1089/ars.2022.0141
155. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–658. doi:10.1111/acel.12344
156. Jiang Y. Osteoarthritis year in review 2021: biology. Osteoarthritis Cartilage. 2022;30(2):207–215. doi:10.1016/j.joca.2021.11.009
157. Xie Y, Zinkle A, Chen L, Mohammadi M. Fibroblast growth factor signalling in osteoarthritis and cartilage repair. Nat Rev Rheumatol. 2020;16(10):547–564. doi:10.1038/s41584-020-0469-2
158. Maruotti N, Corrado A, Cantatore FP. Osteoblast role in osteoarthritis pathogenesis. J Cell Physiol. 2017;232(11):2957–2963. doi:10.1002/jcp.25969
159. Chen X, Gong W, Shao X, et al. METTL3-mediated m(6)A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann Rheum Dis. 2022;81(1):87–99. doi:10.1136/annrheumdis-2021-221091
160. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64(9):1263–1267. doi:10.1136/ard.2004.025270
161. Sanchez-Lopez E, Coras R, Torres A, Lane NE, Guma M. Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol. 2022;18(5):258–275. doi:10.1038/s41584-022-00749-9
162. Wu CL, Harasymowicz NS, Klimak MA, Collins KH, Guilak F. The role of macrophages in osteoarthritis and cartilage repair. Osteoarthritis Cartilage. 2020;28(5):544–554. doi:10.1016/j.joca.2019.12.007
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