Fighting age-related orthopedic diseases: focusing on ferroptosis

Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

Li, J. et al. Ferroptosis: past, present and future. Cell Death Dis. 11, 88 (2020).

Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019).

Fang, X. et al. Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis. Circ. Res. 127, 486–501 (2020).

Fang, X., Ardehali, H., Min, J., & Wang, F. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat. Rev. Cardiol. 20, 7–23 (2023).

Yang, X. et al. Ferroptosis in heart failure. J. Mol. Cell Cardiol. 173, 141–153 (2022).

Wang, H. et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 66, 449–465 (2017).

Chen, J. et al. The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 29, 467–480 (2022).

Tonnus, W. et al. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat. Commun. 12, 4402 (2021).

Lei, G., Zhuang, L. & Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer 22, 381–396 (2022).

Campisi, J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019).

Calcinotto, A. et al. Cellular senescence: aging, cancer, and injury. Physiol. Rev. 99, 1047–1078 (2019).

Wagner, K. H., Cameron-Smith, D., Wessner, B. & Franzke, B. Biomarkers of aging: from function to molecular biology. Nutrients 8, 338 (2016).

Deyo, R. A. & Mirza, S. K. CLINICAL PRACTICE. Herniated lumbar intervertebral disk. N. Engl. J. Med. 374, 1763–1772 (2016).

Wan, M., Gray-Gaillard, E. F. & Elisseeff, J. H. Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration. Bone Res. 9, 41 (2021).

DALYs GBD, Collaborators H. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1859–1922 (2018).

Cieza, A. et al. Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 2006–2017 (2021).

Baldwin, M. J., Cribbs, A. P., Guilak, F. & Snelling, S. J. B. Mapping the musculoskeletal system one cell at a time. Nat. Rev. Rheumatol. 17, 247–248 (2021).

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. 53, 9 (2020).

Jeon, J. et al. TRIM24-RIP3 axis perturbation accelerates osteoarthritis pathogenesis. Ann. Rheum. Dis. 79, 1635–1643 (2020).

An, S., Hu, H., Li, Y. & Hu, Y. Pyroptosis plays a role in osteoarthritis. Aging Dis. 11, 1146–1157 (2020).

Zheng, J. & Conrad, M. The metabolic underpinnings of ferroptosis. Cell Metab. 32, 920–937 (2020).

Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).

Ingold, I. et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422, e421 (2018).

D’Arcy, M. S. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol. Int. 43, 582–592 (2019).

Zhang, Y., Chen, X., Gueydan, C. & Han, J. Plasma membrane changes during programmed cell deaths. Cell Res. 28, 9–21 (2018).

Martinet, W., Knaapen, M. W., Kockx, M. M. & De Meyer, G. R. Autophagy in cardiovascular disease. Trends Mol. Med. 13, 482–491 (2007).

Chen, X. et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res. 26, 1007–1020 (2016).

Frank, D. & Vince, J. E. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 26, 99–114 (2019).

Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).

Gan, B. Mitochondrial regulation of ferroptosis. J. Cell Biol. 220, e202105043 (2021).

Bedoui, S., Herold, M. J. & Strasser, A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat. Rev. Mol. Cell Biol. 21, 678–695 (2020).

Mao, C. et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593, 586–590 (2021).

Wang, F. & Min, J. DHODH tangoing with GPX4 on the ferroptotic stage. Signal Transduct. Target Ther. 6, 244 (2021).

Hu, Q. et al. GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis. Cell Death Dis. 12, 706 (2021).

Yuan, H. et al. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys. Res. Commun. 478, 1338–1343 (2016).

Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).

Sun, X. et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63, 173–184 (2016).

He, S. et al. ACSL4 contributes to ferroptosis-mediated rhabdomyolysis in exertional heat stroke. J. Cachexia Sarcopenia Muscle 13, 1717–1730 (2022).

Tan, S., Schubert, D. & Maher, P. Oxytosis: a novel form of programmed cell death. Curr. Top. Med Chem. 1, 497–506 (2001).

Eaton, J. W. & Qian, M. Molecular bases of cellular iron toxicity. Free Radic. Biol. Med. 32, 833–840 (2002).

Eagle, H., Piez, K. A. & Oyama, V. I. The biosynthesis of cystine in human cell cultures. J. Biol. Chem. 236, 1425–1428 (1961).

Eagle, H. Nutrition needs of mammalian cells in tissue culture. Science 122, 501–514 (1955).

Stockwell, B. R. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022).

Crielaard, B. J., Lammers, T. & Rivella, S. Targeting iron metabolism in drug discovery and delivery. Nat. Rev. Drug Discov. 16, 400–423 (2017).

Yanatori, I. & Kishi, F. DMT1 and iron transport. Free Radic. Biol. Med. 133, 55–63 (2019).

Donovan, A. et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781 (2000).

Donovan, A. et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 1, 191–200 (2005).

Chen, H. et al. Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice. Blood 103, 3933–3939 (2004).

Fuqua, B. K. et al. Severe iron metabolism defects in mice with double knockout of the multicopper ferroxidases hephaestin and ceruloplasmin. Cell Mol. Gastroenterol. Hepatol. 6, 405–427 (2018).

Muckenthaler, M. U., Rivella, S., Hentze, M. W. & Galy, B. A red carpet for iron metabolism. Cell 168, 344–361 (2017).

Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004).

Billesbolle, C. B. et al. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature 586, 807–811 (2020).

Jiang, L. et al. RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation. Blood 138, 689–705 (2021).

Matias, C. et al. Citrate and albumin facilitate transferrin iron loading in the presence of phosphate. J. Inorg. Biochem 168, 107–113 (2017).

Fotticchia, I. et al. Energetics of ligand-receptor binding affinity on endothelial cells: an in vitro model. Colloids Surf. B Biointerfaces 144, 250–256 (2016).

Zhang, F. et al. Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses. Haematologica 97, 1826–1835 (2012).

Dautry-Varsat, A., Ciechanover, A. & Lodish, H. F. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 80, 2258–2262 (1983).

Dong, D. et al. 16 T high static magnetic field inhibits receptor activator of nuclear factor kappa-Beta ligand-induced osteoclast differentiation by regulating iron metabolism in Raw264.7 cells. J. Tissue Eng. Regen. Med 13, 2181–2190 (2019).

Xu, Z. et al. The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss. Bone 94, 152–161 (2017).

Roodman, G. D. Osteoclasts pump iron. Cell Metab. 9, 405–406 (2009).

Ishii, K. A. et al. Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat. Med. 15, 259–266 (2009).

Liuzzi, J. P. et al. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc. Natl Acad. Sci. USA 103, 13612–13617 (2006).

Wang, C. Y. et al. ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J. Biol. Chem. 287, 34032–34043 (2012).

Knutson, M. D. Non-transferrin-bound iron transporters. Free Radic. Biol. Med. 133, 101–111 (2019).

Yu, Y. et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood 136, 726–739 (2020).

Andersen, C. B. et al. Structure of the haptoglobin-haemoglobin complex. Nature 489, 456–459 (2012).

Li, J. Y. et al. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev. Cell 16, 35–46 (2009).

Shaw, G. C. et al. Mitoferrin is essential for erythroid iron assimilation. Nature 440, 96–100 (2006).

Zhang, Z. et al. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118, 1912–1922 (2011).

Zhang, Z. et al. Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice. Hepatology 56, 961–971 (2012).

Gu, Z. et al. Decreased ferroportin promotes myeloma cell growth and osteoclast differentiation. Cancer Res. 75, 2211–2221 (2015).

Wang, L. et al. Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo. J. Biol. Chem. 293, 9248–9264 (2018).

Ledesma-Colunga, M. G. et al. Disruption of the hepcidin/ferroportin regulatory circuitry causes low axial bone mass in mice. Bone 137, 115400 (2020).

Balogh, E., Paragh, G. & Jeney, V. Influence of iron on bone homeostasis. Pharmaceuticals 11, 107 (2018).

Jeney, V. Clinical impact and cellular mechanisms of iron overload-associated bone loss. Front Pharm. 8, 77 (2017).

Soltanoff, C. S., Yang, S., Chen, W. & Li, Y. P. Signaling networks that control the lineage commitment and differentiation of bone cells. Crit. Rev. Eukaryot. Gene Expr. 19, 1–46 (2009).

Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet 4, 638–649 (2003).

Boyce, B. F. & Xing, L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res. Ther. 9(Suppl 1), S1 (2007).

Das, B. K. et al. Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton. Elife 11, e73539 (2022).

Jia, P. et al. Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species. J. Orthop. Res. 30, 1843–1852 (2012).

Hou, J. M., Xue, Y. & Lin, Q. M. Bovine lactoferrin improves bone mass and microstructure in ovariectomized rats via OPG/RANKL/RANK pathway. Acta Pharm. Sin. 33, 1277–1284 (2012).

Tsay, J. et al. Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 116, 2582–2589 (2010).

Guggenbuhl, P. et al. Bone status in a mouse model of genetic hemochromatosis. Osteoporos. Int. 22, 2313–2319 (2011).

Tang, Y. et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med. 15, 757–765 (2009).

Kim, W. J. et al. RUNX2-modifying enzymes: therapeutic targets for bone diseases. Exp. Mol. Med. 52, 1178–1184 (2020).

Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997).

Lertsuwan, K. et al. Differential effects of Fe²⁺ and Fe³⁺ on osteoblasts and the effects of 1,25(OH)₂D₃, deferiprone and extracellular calcium on osteoblast viability under iron-overloaded conditions. PLoS One 15, e0234009 (2020).

Yang, Q., Jian, J., Abramson, S. B. & Huang, X. Inhibitory effects of iron on bone morphogenetic protein 2-induced osteoblastogenesis. J. Bone Min. Res. 26, 1188–1196 (2011).

Balogh, E. et al. Iron overload inhibits osteogenic commitment and differentiation of mesenchymal stem cells via the induction of ferritin. Biochim Biophys. Acta 1862, 1640–1649 (2016).

Chen, Y. C. et al. The inhibitory effect of superparamagnetic iron oxide nanoparticle (Ferucarbotran) on osteogenic differentiation and its signaling mechanism in human mesenchymal stem cells. Toxicol. Appl. Pharm. 245, 272–279 (2010).

Chang, Y. K. et al. Amine-surface-modified superparamagnetic iron oxide nanoparticles interfere with differentiation of human mesenchymal stem cells. J. Orthop. Res. 30, 1499–1506 (2012).

Messer, J. G., Kilbarger, A. K., Erikson, K. M. & Kipp, D. E. Iron overload alters iron-regulatory genes and proteins, down-regulates osteoblastic phenotype, and is associated with apoptosis in fetal rat calvaria cultures. Bone 45, 972–979 (2009).

Toxqui, L. & Vaquero, M. P. Chronic iron deficiency as an emerging risk factor for osteoporosis: a hypothesis. Nutrients 7, 2324–2344 (2015).

Zofkova, I., Davis, M. & Blahos, J. Trace elements have beneficial, as well as detrimental effects on bone homeostasis. Physiol. Res. 66, 391–402 (2017).

Katsumata, S., Katsumata-Tsuboi, R., Uehara, M. & Suzuki, K. Severe iron deficiency decreases both bone formation and bone resorption in rats. J. Nutr. 139, 238–243 (2009).

Diaz-Castro, J. et al. Severe nutritional iron-deficiency anaemia has a negative effect on some bone turnover biomarkers in rats. Eur. J. Nutr. 51, 241–247 (2012).

Wright, I. et al. Bone remodelling is reduced by recovery from iron-deficiency anaemia in premenopausal women. J. Physiol. Biochem. 69, 889–896 (2013).

Blanco-Rojo, R. et al. Relationship between vitamin D deficiency, bone remodelling and iron status in iron-deficient young women consuming an iron-fortified food. Eur. J. Nutr. 52, 695–703 (2013).

Zhao, G. Y. et al. A comparison of the biological activities of human osteoblast hFOB1.19 between iron excess and iron deficiency. Biol. Trace Elem. Res. 150, 487–495 (2012).

Cui, J. et al. Osteocytes in bone aging: advances, challenges, and future perspectives. Ageing Res. Rev. 77, 101608 (2022).

Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).

Yang, J. et al. Iron overload-induced osteocyte apoptosis stimulates osteoclast differentiation through increasing osteocytic RANKL production in vitro. Calcif. Tissue Int. 107, 499–509 (2020).

Park, C. H., Valore, E. V. & Waring, A. J. Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276, 7806–7810 (2001).

Pasricha, S. R., Tye-Din, J., Muckenthaler, M. U. & Swinkels, D. W. Iron deficiency. Lancet 397, 233–248 (2021).

Peyssonnaux, C. et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J. Clin. Investig. 117, 1926–1932 (2007).

Shah, Y. M. & Xie, L. Hypoxia-inducible factors link iron homeostasis and erythropoiesis. Gastroenterology 146, 630–642 (2014).

Hirota, K. An intimate crosstalk between iron homeostasis and oxygen metabolism regulated by the hypoxia-inducible factors (HIFs). Free Radic. Biol. Med. 133, 118–129 (2019).

Robach, P. et al. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin. Blood 113, 6707–6715 (2009).

Kautz, L. et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46, 678–684 (2014).

Coffey, R. et al. Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice. Blood 139, 439–451 (2022).

Wrighting, D. M. & Andrews, N. C. Interleukin-6 induces hepcidin expression through STAT3. Blood 108, 3204–3209 (2006).

Mayeur, C. et al. The type I BMP receptor Alk3 is required for the induction of hepatic hepcidin gene expression by interleukin-6. Blood 123, 2261–2268 (2014).

Hentze, M. W., Muckenthaler, M. U., Galy, B. & Camaschella, C. Two to tango: regulation of Mammalian iron metabolism. Cell 142, 24–38 (2010).

Zhou, Y. et al. Irp2 knockout causes osteoporosis by inhibition of bone remodeling. Calcif. Tissue Int. 104, 70–78 (2019).

den Elzen, W. P. et al. Plasma hepcidin levels and anemia in old age. The Leiden 85-Plus Study. Haematologica 98, 448–454 (2013).

Liu, B. et al. Association between body iron status and leukocyte telomere length, a biomarker of biological aging, in a nationally representative sample of US adults. J. Acad. Nutr. Diet. 119, 617–625 (2019).

Hohn, A., Jung, T., Grimm, S. & Grune, T. Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radic. Biol. Med. 48, 1100–1108 (2010).

Zeidan, R. S., Han, S. M., Leeuwenburgh, C. & Xiao, R. Iron homeostasis and organismal aging. Ageing Res. Rev. 72, 101510 (2021).

Burton, L. H., Radakovich, L. B., Marolf, A. J. & Santangelo, K. S. Systemic iron overload exacerbates osteoarthritis in the strain 13 guinea pig. Osteoarthr. Cartil. 28, 1265–1275 (2020).

Jing, X. 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 25, 5671–5680 (2021).

Yao, X. et al. Chondrocyte ferroptosis contribute to the progression of osteoarthritis. J. Orthop. Transl. 27, 33–43 (2021).

Zhang, H. et al. Hepcidin-induced reduction in iron content and PGC-1beta expression negatively regulates osteoclast differentiation to play a protective role in postmenopausal osteoporosis. Aging 13, 11296–11314 (2021).

Zhao, L. et al. Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character. J. Nutr. Biochem. 26, 1174–1182 (2015).

Zhang, Y. et al. Effects of iron overload on the bone marrow microenvironment in mice. PLoS One 10, e0120219 (2015).

Telfer, J. F. & Brock, J. H. Proinflammatory cytokines increase iron uptake into human monocytes and synovial fibroblasts from patients with rheumatoid arthritis. Med. Sci. Monit. 10, BR91–BR95 (2004).

Valentino, L. A. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J. Thromb. Haemost. 8, 1895–1902 (2010).

Yang, Y. et al. Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis. Bone Res. 10, 26 (2022).

Camaschella, C. et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat. Genet 25, 14–15 (2000).

Pietrangelo, A. The ferroportin disease. Blood Cells Mol. Dis. 32, 131–138 (2004).

Valenti, L. et al. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos. Int. 20, 549–555 (2009).

Simao, M. & Cancela, M. L. Musculoskeletal complications associated with pathological iron toxicity and its molecular mechanisms. Biochem Soc. Trans. 49, 747–759 (2021).

Dede, A. D. et al. Thalassemia-associated osteoporosis: a systematic review on treatment and brief overview of the disease. Osteoporos. Int. 27, 3409–3425 (2016).

Handattu, K. et al. Metabolic bone disease in children with transfusion-dependent Thalassemia. Indian Pediatr. 59, 920–923 (2022).

Ekbote, V. et al. Increased prevalence of fractures in inadequately transfused and chelated Indian children and young adults with beta thalassemia major. Bone 143, 115649 (2021).

Wong, P. et al. Thalassemia bone disease: a 19-year longitudinal analysis. J. Bone Min. Res. 29, 2468–2473 (2014).

Saki, N. et al. Molecular aspects of bone resorption in beta-Thalassemia Major. Cell J. 17, 193–200 (2015).

Simao, M. et al. Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosis. PLoS One 13, e0207441 (2018).

Doyard, M. et al. Decreased bone formation explains osteoporosis in a genetic mouse model of hemochromatosiss. PLoS One 11, e0148292 (2016).

Zarjou, A. et al. Ferritin ferroxidase activity: a potent inhibitor of osteogenesis. J. Bone Min. Res. 25, 164–172 (2010).

Lin, Y. et al. Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss. FASEB J. 36, e22147 (2022).

Tonelli, C., Chio, I. I. C. & Tuveson, D. A. Transcriptional regulation by Nrf2. Antioxid. Redox Signal. 29, 1727–1745 (2018).

Wang, X. et al. Mitochondrial ferritin deficiency promotes osteoblastic ferroptosis via mitophagy in type 2 diabetic osteoporosis. Biol. Trace Elem. Res. 200, 298–307 (2022).

Lu, J. et al. Extracellular vesicles from endothelial progenitor cells prevent steroid-induced osteoporosis by suppressing the ferroptotic pathway in mouse osteoblasts based on bioinformatics evidence. Sci. Rep. 9, 16130 (2019).

Sun, K. et al. Iron homeostasis in arthropathies: from pathogenesis to therapeutic potential. Ageing Res. Rev. 72, 101481 (2021).

Yang, J. et al. Targeting cell death: pyroptosis, ferroptosis, apoptosis and necroptosis in osteoarthritis. Front Cell Dev. Biol. 9, 789948 (2022).

Cai, C., Hu, W. & Chu, T. Interplay between iron overload and osteoarthritis: clinical significance and cellular mechanisms. Front Cell Dev. Biol. 9, 817104 (2021).

Kennish, L. 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. 15, 8 (2014).

Chen, B. et al. Reducing iron accumulation: a potential approach for the prevention and treatment of postmenopausal osteoporosis. Exp. Ther. Med. 10, 7–11 (2015).

Ko, S. H. & Kim, H. S. Menopause-associated lipid metabolic disorders and foods beneficial for postmenopausal women. Nutrients 12, 202 (2020).

Ke, Y. et al. Features and outcomes of elderly rheumatoid arthritis: does the age of onset matter? A comparative study from a single center in China. Rheumatol. Ther. 8, 243–254 (2021).

Park, S. K., Ryoo, J. H., Kim, M. G. & Shin, J. Y. Association of serum ferritin and the development of metabolic syndrome in middle-aged Korean men: a 5-year follow-up study. Diabetes Care 35, 2521–2526 (2012).

Zhang, Y. et al. Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and whites in the United States: The Beijing Osteoarthritis Study. Arthritis Rheum. 44, 2065–2071 (2001).

Bhat, V. et al. Vascular remodeling underlies rebleeding in hemophilic arthropathy. Am. J. Hematol. 90, 1027–1035 (2015).

van Vulpen, L. F. D., Holstein, K. & Martinoli, C. Joint disease in haemophilia: Pathophysiology, pain and imaging. Haemophilia 24(Suppl 6), 44–49 (2018).

Heiland, G. R. et al. Synovial immunopathology in haemochromatosis arthropathy. Ann. Rheum. Dis. 69, 1214–1219 (2010).

Richette, P. et al. Increase in type II collagen turnover after iron depletion in patients with hereditary haemochromatosis. Rheumatology 49, 760–766 (2010).

Wu, L. et al. Association between iron intake and progression of knee osteoarthritis. Nutrients 14, 1674 (2022).

Xu, J. et al. Genetic causal association between iron status and osteoarthritis: a two-sample Mendelian randomization. Nutrients 14, 3683 (2022).

Camacho, A. et al. Iron overload in a murine model of hereditary hemochromatosis is associated with accelerated progression of osteoarthritis under mechanical stress. Osteoarthr. Cartil. 24, 494–502 (2016).

Geib, T. et al. Identification of 4-hydroxynonenal-modified proteins in human osteoarthritic chondrocytes. J. Proteom. 232, 104024 (2021).

Radakovich, L. B. et al. Systemic iron reduction via an iron deficient diet decreases the severity of knee cartilage lesions in the Dunkin-Hartley guinea pig model of osteoarthritis. Osteoarthr. Cartil. 30, 1482–1494 (2022).

Simao, M. et al. Intracellular iron uptake is favored in Hfe-KO mouse primary chondrocytes mimicking an osteoarthritis-related phenotype. Biofactors 45, 583–597 (2019).

Miao, Y. et al. Contribution of ferroptosis and GPX4’s dual functions to osteoarthritis progression. EBioMedicine 76, 103847 (2022).

Luo, H. & Zhang, R. Icariin enhances cell survival in lipopolysaccharide-induced synoviocytes by suppressing ferroptosis via the Xc-/GPX4 axis. Exp. Ther. Med 21, 72 (2021).

Mo, Z., Xu, P. & Li, H. Stigmasterol alleviates interleukin-1beta-induced chondrocyte injury by down-regulatingsterol regulatory element binding transcription factor 2 to regulateferroptosis. Bioengineered 12, 9332–9340 (2021).

Zhou, X. et al. D-mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF-2alpha-dependent manner. Cell Prolif. 54, e13134 (2021).

Zhang, J. et al. Deferoxamine inhibits iron-uptake stimulated osteoclast differentiation by suppressing electron transport chain and MAPKs signaling. Toxicol. Lett. 313, 50–59 (2019).

Liu, F. et al. Regulation of DMT1 on autophagy and apoptosis in osteoblast. Int. J. Med. Sci. 14, 275–283 (2017).

Wang, L. et al. Revealing the immune infiltration landscape and identifying diagnostic biomarkers for lumbar disc herniation. Front Immunol. 12, 666355 (2021).

Yao, M. et al. A comparison between the low back pain scales for patients with lumbar disc herniation: validity, reliability, and responsiveness. Health Qual. Life Outcomes 18, 175 (2020).

Henry, N. et al. Innovative strategies for intervertebral disc regenerative medicine: From cell therapies to multiscale delivery systems. Biotechnol. Adv. 36, 281–294 (2018).

Le Maitre, C. L., Binch, A. L., Thorpe, A. A. & Hughes, S. P. Degeneration of the intervertebral disc with new approaches for treating low back pain. J. Neurosurg. Sci. 59, 47–61 (2015).

Qiu, C. et al. Differential proteomic analysis of fetal and geriatric lumbar nucleus pulposus: immunoinflammation and age-related intervertebral disc degeneration. BMC Musculoskelet. Disord. 21, 339 (2020).

Shamji, M. F. et al. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum. 62, 1974–1982 (2010).

Yang, R. Z. et al. Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis. J. Cell Physiol. 236, 2725–2739 (2021).

Wang, W. et al. Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes. Free Radic. Biol. Med. 190, 234–246 (2022).

Zhang, Y. et al. Single-cell RNA-seq analysis identifies unique chondrocyte subsets and reveals involvement of ferroptosis in human intervertebral disc degeneration. Osteoarthr. Cartil. 29, 1324–1334 (2021).

Zhang, X. et al. Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4. Free Radic. Biol. Med 160, 552–565 (2020).

Lu, S. et al. Ferroportin-dependent iron homeostasis protects against oxidative stress-induced nucleus pulposus cell ferroptosis and ameliorates intervertebral disc degeneration in vivo. Oxid. Med. Cell Longev. 2021, 6670497 (2021).

Bin, S. et al. Targeting miR-10a-5p/IL-6R axis for reducing IL-6-induced cartilage cell ferroptosis. Exp. Mol. Pathol. 118, 104570 (2021).

Xiao, Z. F. et al. Mechanics and biology interact in intervertebral disc degeneration: a novel composite mouse model. Calcif. Tissue Int. 106, 401–414 (2020).

Shan, L. et al. Increased hemoglobin and heme in MALDI-TOF MS analysis induce ferroptosis and promote degeneration of herniated human nucleus pulposus. Mol. Med. 27, 103 (2021).

Xie, Y. et al. Ferroptosis: process and function. Cell Death Differ. 23, 369–379 (2016).

Cotticelli, M. G. et al. Ferroptosis as a novel therapeutic target for Friedreich’s ataxia. J. Pharm. Exp. Ther. 369, 47–54 (2019).

Li, J. et al. New target in an old enemy: herbicide (R)-dichlorprop induces ferroptosis-like death in plants. J. Agric Food Chem. 69, 7554–7564 (2021).

Zhou, J. et al. Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma. Cell Oncol. 43, 461–475 (2020).

Zhang, Y. et al. Ferroptosis inhibitor SRS 16-86 attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury. Brain Res. 1706, 48–57 (2019).

Li, Y. et al. Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury. Cell Death Differ. 27, 2635–2650 (2020).

Hinman, A. et al. Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS One 13, e0201369 (2018).

Wu, Y. et al. The potential role of ferroptosis in neonatal brain injury. Front Neurosci. 13, 115 (2019).

Dai, C. et al. Transcription factors in ferroptotic cell death. Cancer Gene Ther. 27, 645–656 (2020).

Louandre, C. et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int. J. Cancer 133, 1732–1742 (2013).

Su, Y. et al. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett. 483, 127–136 (2020).

Feng, H. & Stockwell, B. R. Unsolved mysteries: how does lipid peroxidation cause ferroptosis? PLoS Biol. 16, e2006203 (2018).

Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

Lorincz, T. et al. Ferroptosis is involved in acetaminophen induced cell death. Pathol. Oncol. Res. 21, 1115–1121 (2015).

Hassannia, B. et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Invest. 128, 3341–3355 (2018).

Yang, W. S. et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl. Acad. Sci. USA 113, E4966–E4975 (2016).

Ding, H. et al. Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis. J. Cachexia Sarcopenia Muscle 12, 746–768 (2021).

Garcia-Casal, M. N. et al. Serum or plasma ferritin concentration as an index of iron deficiency and overload. Cochrane Database Syst. Rev. 5, CD011817 (2021).

von Haehling, S. et al. Iron deficiency in heart failure: an overview. JACC Heart Fail 7, 36–46 (2019).

Garcia-Casal, M. N. et al. Are current serum and plasma ferritin cut-offs for iron deficiency and overload accurate and reflecting iron status? A systematic review. Arch. Med. Res. 49, 405–417 (2018).

Ebrahimpour, L. et al. Correlation between bone mineral densitometry and liver/heart iron overload evaluated by quantitative T2* MRI. Hematology 17, 297–301 (2012).

Shah, F. et al. Relationship between Serum Ferritin and Outcomes in beta-Thalassemia: A systematic literature review. J. Clin. Med. 11, 4448 (2022).

Costa, S. A., Ribeiro, C. C. C., Moreira, A. R. O. & Carvalho Souza, S. F. High serum iron markers are associated with periodontitis in post-menopausal women: a population-based study (NHANES III). J. Clin. Periodontol. 49, 221–229 (2022).

Jian, J., Pelle, E. & Huang, X. Iron and menopause: does increased iron affect the health of postmenopausal women? Antioxid. Redox Signal. 11, 2939–2943 (2009).

Richette, P., Ottaviani, S., Vicaut, E. & Bardin, T. Musculoskeletal complications of hereditary hemochromatosis: a case-control study. J. Rheumatol. 37, 2145–2150 (2010).

Mobarra, N. et al. A review on iron chelators in treatment of iron overload syndromes. Int. J. Hematol. Oncol. Stem Cell Res. 10, 239–247 (2016).

Pennell, D. J. et al. Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with beta-thalassemia major. Haematologica 97, 842–848 (2012).

Wood, J. C. et al. The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores. Blood 116, 537–543 (2010).

Deugnier, Y. et al. Improvement in liver pathology of patients with beta-thalassemia treated with deferasirox for at least 3 years. Gastroenterology 141, 1202–1211 (2011).

Maggio, A. et al. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial. Lancet Haematol. 7, e469–e478 (2020).

Yesilipek, M. A. et al. A phase II, multicenter, single-arm study to evaluate the safety and efficacy of deferasirox after hematopoietic stem cell transplantation in children with beta-Thalassemia Major. Biol. Blood Marrow Transpl. 24, 613–618 (2018).

Jing, X. et al. Iron overload is associated with accelerated progression of osteoarthritis: the role of DMT1 mediated iron homeostasis. Front. Cell Dev. Biol. 8, 594509 (2021).

Poggi, M. et al. Longitudinal changes of endocrine and bone disease in adults with beta-thalassemia major receiving different iron chelators over 5 years. Ann. Hematol. 95, 757–763 (2016).

Casale, M. et al. Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with beta-thalassemia major. Am. J. Hematol. 89, 1102–1106 (2014).

Bordbar, M. et al. Effect of different iron chelation regimens on bone mass in transfusion-dependent thalassemia patients. Expert Rev. Hematol. 12, 997–1003 (2019).

Sridharan, K. & Sivaramakrishnan, G. Efficacy and safety of iron chelators in thalassemia and sickle cell disease: a multiple treatment comparison network meta-analysis and trial sequential analysis. Expert Rev. Clin. Pharm. 11, 641–650 (2018).

Lin, C. H. et al. Therapeutic mechanism of combined oral chelation therapy to maximize efficacy of iron removal in transfusion-dependent thalassemia major - a pilot study. Expert Rev. Hematol. 12, 265–272 (2019).

Baschant, U. et al. Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors. Haematologica 101, 1499–1507 (2016).

Jing, X. et al. Calcium chelator BAPTAAM protects against iron overloadinduced chondrocyte mitochondrial dysfunction and cartilage degeneration. Int J. Mol. Med 48, 196 (2021).

Casale, M. et al. Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort. Haematologica 107, 467–477 (2022).

Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).

Golej, D. L. et al. Long-chain acyl-CoA synthetase 4 modulates prostaglandin E(2) release from human arterial smooth muscle cells. J. Lipid Res. 52, 782–793 (2011).

Jin, Z. L. et al. Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis. ASN Neuro 13, 17590914211010647 (2021).

Askari, B. et al. Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator-activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes 56, 1143–1152 (2007).

Xu, Y. et al. Inhibition of ACSL4 attenuates ferroptotic damage after pulmonary ischemia-reperfusion. FASEB J. 34, 16262–16275 (2020).

Fahmi, H. et al. Peroxisome proliferator-activated receptor gamma activators inhibit MMP-1 production in human synovial fibroblasts likely by reducing the binding of the activator protein 1. Osteoarthr. Cartil. 10, 100–108 (2002).

Kim, D. H. et al. PPAR-delta agonist affects adipo-chondrogenic differentiation of human mesenchymal stem cells through the expression of PPAR-gamma. Regen. Ther. 15, 103–111 (2020).

Saul, D. et al. Effect of the lipoxygenase-inhibitors baicalein and zileuton on the vertebra in ovariectomized rats. Bone 101, 134–144 (2017).

Alvaro-Gracia, J. M. Licofelone-clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. Rheumatology 43(Suppl 1), i21–i25 (2004).

Boileau, C. et al. The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway. Ann. Rheum. Dis. 64, 891–898 (2005).

Yabas, M. et al. A next generation formulation of curcumin ameliorates experimentally induced osteoarthritis in rats via regulation of inflammatory mediators. Front Immunol. 12, 609629 (2021).

Gruenwald, J., Uebelhack, R. & More, M. I. Rosa canina - Rose hip pharmacological ingredients and molecular mechanics counteracting osteoarthritis - a systematic review. Phytomedicine 60, 152958 (2019).

Sato, H., Tamba, M., Ishii, T. & Bannai, S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J. Biol. Chem. 274, 11455–11458 (1999).

Liu, M. R., Zhu, W. T. & Pei, D. S. System Xc(-): a key regulatory target of ferroptosis in cancer. Investig. N. Drugs 39, 1123–1131 (2021).

Koppula, P., Zhang, Y., Zhuang, L. & Gan, B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun. 38, 12 (2018).

Cao, J. Y. & Dixon, S. J. Mechanisms of ferroptosis. Cell Mol. Life Sci. 73, 2195–2209 (2016).

Ursini, F. & Maiorino, M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic. Biol. Med. 152, 175–185 (2020).

Zhao, Y. et al. The role of erastin in ferroptosis and its prospects in cancer therapy. Onco Targets Ther. 13, 5429–5441 (2020).

Yan, R. et al. The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis. Cell Res. 32, 687–690 (2022).

Tang, L., Zhang, Y., Qian, Z. & Shen, X. The mechanism of Fe²⁺-initiated lipid peroxidation in liposomes: the dual function of ferrous ions, the roles of the pre-existing lipid peroxides and the lipid peroxyl radical. Biochem. J. 352(Pt 1), 27–36 (2000).

Forcina, G. C. & Dixon, S. J. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics 19, e1800311 (2019).

Forman, H. J., Zhang, H. & Rinna, A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol. Asp. Med 30, 1–12 (2009).

Zhang, Y. et al. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat. Commun. 12, 1589 (2021).

Sui, X. et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Front. Pharm. 9, 1371 (2018).

Orsolic, N. et al. Antioxidative and anti-inflammatory activities of chrysin and naringenin in a drug-induced bone loss model in rats. Int. J. Mol. Sci. 23, 2872 (2022).

Huang, Q. et al. Ginsenoside-Rb2 displays anti-osteoporosis effects through reducing oxidative damage and bone-resorbing cytokines during osteogenesis. Bone 66, 306–314 (2014).

Huang, Q. et al. Protective effects of myricitrin against osteoporosis via reducing reactive oxygen species and bone-resorbing cytokines. Toxicol. Appl Pharm. 280, 550–560 (2014).

Ghareghani, M. et al. Melatonin therapy reduces the risk of osteoporosis and normalizes bone formation in multiple sclerosis. Fundam. Clin. Pharm. 32, 181–187 (2018).

Ma, H. et al. Melatonin suppresses ferroptosis induced by high glucose via activation of the Nrf2/HO-1 signaling pathway in type 2 diabetic osteoporosis. Oxid. Med. Cell Longev. 2020, 9067610 (2020).

Garikipati, V. N. S. & Kishore, R. Induced pluripotent stem cells derived extracellular vesicles: a potential therapy for cardiac repair. Circ. Res. 122, 197–198 (2018).

Jung, J. H., Fu, X. & Yang, P. C. Exosomes generated from iPSC-derivatives: new direction for stem cell therapy in human heart diseases. Circ. Res. 120, 407–417 (2017).

Qiu, L., Luo, Y. & Chen, X. Quercetin attenuates mitochondrial dysfunction and biogenesis via upregulated AMPK/SIRT1 signaling pathway in OA rats. Biomed. Pharmacother. 103, 1585–1591 (2018).

Yao, J. et al. Nifedipine inhibits oxidative stress and ameliorates osteoarthritis by activating the nuclear factor erythroid-2-related factor 2 pathway. Life Sci. 253, 117292 (2020).

Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).

Zhang, X. X. et al. Efficacy of coenzyme Q10 in mitigating spinal cord injury-induced osteoporosis. Mol. Med. Rep. 12, 3909–3915 (2015).

Varela-Lopez, A. et al. Age-related loss in bone mineral density of rats fed lifelong on a fish oil-based diet Is avoided by coenzyme Q10 addition. Nutrients 9, 176 (2017).

Jhun, J. et al. Liposome/gold hybrid nanoparticle encoded with CoQ10 (LGNP-CoQ10) suppressed rheumatoid arthritis via STAT3/Th17 targeting. PLoS One 15, e0241080 (2020).

Nachvak, S. M. et al. Effects of coenzyme Q10 supplementation on matrix metalloproteinases and DAS-28 in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled clinical trial. Clin. Rheumatol. 38, 3367–3374 (2019).

Jhun, J. et al. Coenzyme Q10 suppresses Th17 cells and osteoclast differentiation and ameliorates experimental autoimmune arthritis mice. Immunol. Lett. 166, 92–102 (2015).

Lee, J. et al. Coenzyme Q10 ameliorates pain and cartilage degradation in a rat model of osteoarthritis by regulating nitric oxide and inflammatory cytokines. PLoS One 8, e69362 (2013).

Tabas, I. & Ron, D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol. 13, 184–190 (2011).

Dixon, S. J. et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3, e02523 (2014).

Hong, S. H. et al. Molecular crosstalk between ferroptosis and apoptosis: emerging role of ER stress-induced p53-independent PUMA expression. Oncotarget 8, 115164–115178 (2017).

Ge, W. et al. Advanced glycation end products promote osteoporosis by inducing ferroptosis in osteoblasts. Mol. Med. Rep. 25, 140 (2022).

Gruber, H. E. et al. Spontaneous age-related cervical disc degeneration in the sand rat. Clin. Orthop. Relat. Res. 472, 1936–1942 (2014).

Jiang, W. et al. SIRT1 protects against apoptosis by promoting autophagy in degenerative human disc nucleus pulposus cells. Sci. Rep. 4, 7456 (2014).

Madhu, V., Guntur, A. R. & Risbud, M. V. Role of autophagy in intervertebral disc and cartilage function: implications in health and disease. Matrix Biol. 100-101, 207–220 (2021).

Rashid, H. O., Yadav, R. K., Kim, H. R. & Chae, H. J. ER stress: autophagy induction, inhibition and selection. Autophagy 11, 1956–1977 (2015).

Lee, Y. S. et al. Ferroptotic agent-induced endoplasmic reticulum stress response plays a pivotal role in the autophagic process outcome. J. Cell Physiol. 235, 6767–6778 (2020).

Mancias, J. D. et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).

Gao, M. et al. Ferroptosis is an autophagic cell death process. Cell Res. 26, 1021–1032 (2016).

Hou, W. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12, 1425–1428 (2016).

Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).

Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).

Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116 (2016).

Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).

Crawford, E. D. & Wells, J. A. Caspase substrates and cellular remodeling. Annu. Rev. Biochem. 80, 1055–1087 (2011).

Li, Z. et al. P2X7 receptor induces pyroptotic inflammation and cartilage degradation in osteoarthritis via NF-kappaB/NLRP3 crosstalk. Oxid. Med. Cell Longev. 2021, 8868361 (2021).

Tao, Z. et al. Pyroptosis in osteoblasts: a novel hypothesis underlying the pathogenesis of osteoporosis. Front Endocrinol. (Lausanne) 11, 548812 (2020).

Zhai, Z. et al. Attenuation of rheumatoid arthritis through the inhibition of tumor necrosis factor-induced caspase 3/gasdermin E-mediated pyroptosis. Arthritis Rheumatol. 74, 427–440 (2022).

Tang, R. et al. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J. Hematol. Oncol. 13, 110 (2020).

Zhou, Z. et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science 368, eaaz7548 (2020).

Wang, W. et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).

Lang, X. et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 9, 1673–1685 (2019).

Vats, K. et al. Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure. Redox Biol. 47, 102143 (2021).

Cao, Z. et al. Crosstalk of pyroptosis, ferroptosis, and mitochondrial aldehyde dehydrogenase 2-related mechanisms in sepsis-induced lung injury in a mouse model. Bioengineered 13, 4810–4820 (2022).

Wu, C. et al. Induction of ferroptosis and mitochondrial dysfunction by oxidative stress in PC12 cells. Sci. Rep. 8, 574 (2018).

Battaglia, A. M. et al. Ferroptosis and cancer: mitochondria meet the “Iron Maiden” cell death. Cells 9, 1505 (2020).

Wu, X., Li, Y., Zhang, S. & Zhou, X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics 11, 3052–3059 (2021).