Targeting Ferroptosis in Bone-Related Diseases: Facts and Perspectives

Figures & data

Figure 1 Iron transport and ferroptosis. Iron from different sources is converted to Fe³⁺ in enterocytes or macrophages and transported by transferrin to target cells. Intracellular iron overload can promote ferroptosis by increasing ROS and lipid peroxidation through the Fenton reaction.

Abbreviations: DCYTB, duodenal cytochrome B; DMT1, divalent metal transporter 1; FPN1, ferroportin 1; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; HEPH, hephaestin; HO-1, heme oxygenase-1; NCOA4, nuclear receptor coactivator 4; ROS, reactive oxygen species; STEAP3, six transmembrane epithelial antigen of the prostate 3; TF, transferrin; TFR1, transferrin receptor 1.

Figure 2 Mechanisms and important regulatory signaling pathways of ferroptosis.

Abbreviations: ACSL4, acyl-CoA synthetase long-chain family member 4; ALOX15, arachidonate lipoxygenase 15; AMPK, AMP-activated protein kinase; Akt, protein kinase B; BH₄, tetrahydrobiopterin; CoQ10, coenzyme Q10; Cys, cysteine; Cys2, cysteine; DDP4, dipeptidyl peptidase-4; ECAD, E-cadherin; 4EBP, eukaryotic initiation factor 4E-binding proteins; FPN1, ferroportin 1; FSP1, ferroptosis suppressor protein 1; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; GCH1, GTP cyclohydrolase-1; GLS2, glutaminase 2; Glu, glutamate; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; HO-1, heme oxygenase-1; Keap1, Kelch-like ECH-associated protein 1; LPCAT3, lysophosphatidylcholine acyltransferase 3; mTOR, mammalian target of rapamycin; MUFA, monounsaturated fatty acyl; NCOA4, nuclear receptor coactivator 4; NF2, neurofibromatosis 2; NOX, NADPH oxidase; Nrf2, nuclear factor E2-related factor 2; PI3K, phosphatidylinositol-3 kinase; PL, phospholipid; PLOO, phospholipid peroxyl radical; PUFA, polyunsaturated fatty acyl; ROS, reactive oxygen species; SAT1, spermidine/spermine N1-acetyltransferase 1; SCD1, stearoyl-CoA desaturase-1; SLC7A11, subunit solute carrier family 7 member 11; TAZ, WW domain-containing transcription regulator protein 1; TFR1, transferrin receptor 1; YAP, yes-associated protein 1.

Table 1 Several Regulators of Ferroptosis

	Regulator	Mechanism	References
Inducer	p53	Inhibiting SLC7A11 expression and GSH biosynthesis	[44–47]
		Promoting ALOX15 expression and lipid peroxidation	[48]
		Promoting GLS2 transcription, converting glutamate to α-ketoglutarate, and increasing ROS	[49]
	HO-1	Degrading hemosiderin and producing Fe^2+	[61]
	AMPK	Inhibiting system XC-	[65]
		Inhibiting SCD1, reducing MUFA production to promote PUFA	[66,67]
	Hippo	Promoting NOX2/4 expression	[79,80]
Inhibitor	p53	Promoting p21 transcription and increasing GSH production	[52]
		Inhibiting the binding of DDP4 to NOX1	[53]
	Nrf2	Promoting FTL/FTH1 expression	[56]
		Promoting SLC7A11 and GPX4 synthesis	[57,58]
	HO-1	Promoting GPX4 and NADPH production	[60]
	AMPK	Inducing Nrf2 activation and promoting antioxidant function	[68,69]
		Inhibiting ACC1 and reducing PUFA biosynthesis	[71]
	mTOR	Promoting SCD1 expression, leading to increased MUFA and PUFA substitution	[85]
		Promoting GPX4 synthesis	[87]

Abbreviations: ACC1, acetyl-CoA carboxylases 1; ALOX15, arachidonate lipoxygenase 15; AMPK, AMP-activated protein kinase; DDP4, dipeptidyl peptidase-4; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; GLS2, glutaminase 2; GPX4, glutathione peroxidase 4; GSH, glutathione; HO-1, heme oxygenase-1; mTOR, mammalian target of rapamycin; MUFA, monounsaturated fatty acyl; NOX, NADPH oxidase; Nrf2, nuclear factor E2-related factor 2; PUFA, polyunsaturated fatty acyl; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase-1; SLC7A11, subunit solute carrier family 7 member 11.

Figure 3 Ferroptosis is involved in the pathogenesis of various bone-related diseases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, and osteosarcoma.

Abbreviations: BMSC, bone marrow-derived mesenchymal stem cell; ECM, extracellular matrix; Fer-1, ferrostatin-1; FLS, fibroblast-like synoviocyte; FPN1, ferroportin 1; GPX4, glutathione peroxidase 4; GSH, glutathione; HIF-1α, hypoxia-inducible factors; Nrf2, nuclear factor E2-related factor 2; OB, osteoblast; OC, osteoclast; RANKL, receptor activator of the nuclear factor-κB ligand; ROS, reactive oxygen species; Runx2, Runt-related transcription factor 2; SCD1, stearoyl-CoA desaturase-1; SEMA5A, semaphorin 5A; SLC7A11, subunit solute carrier family 7 member 11; STAT3, signal transducer and activator of transcription 3.

Ma XH, Liu JH, Liu CY, et al. Alox15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage. Signal Transduct Target Ther. 2022;7(1):288. doi:10.1038/s41392-022-01090-z

 PubMed Web of Science ®Google Scholar

Kang R, Kroemer G, Tang D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med. 2019;133:162–168. doi:10.1016/j.freeradbiomed.2018.05.074

 PubMed Web of Science ®Google Scholar

Rochette L, Zeller M, Cottin Y, Vergely C. Redox functions of heme oxygenase-1 and biliverdin reductase in diabetes. Trends Endocrinol Metab. 2018;29(2):74–85. doi:10.1016/j.tem.2017.11.005

 PubMed Web of Science ®Google Scholar

Song X, Zhu S, Chen P, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system X(c)(-) activity. Curr Biol. 2018;28(15):2388–2399 e5. doi:10.1016/j.cub.2018.05.094

 PubMed Web of Science ®Google Scholar

Liu MY, Li HM, Wang XY, et al. TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway. Free Radic Biol Med. 2022;182:219–231. doi:10.1016/j.freeradbiomed.2022.03.002

 PubMed Web of Science ®Google Scholar

Zhao Y, Li M, Yao X, et al. Hcar1/mct1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep. 2020;33(10):108487. doi:10.1016/j.celrep.2020.108487

 PubMed Web of Science ®Google Scholar

Yang WH, Huang Z, Wu J, Ding CC, Murphy SK, Chi JT. A taz-angptl4-nox2 axis regulates ferroptotic cell death and chemoresistance in epithelial ovarian cancer. Mol Cancer Res. 2020;18(1):79–90. doi:10.1158/1541-7786.MCR-19-0691

 PubMed Web of Science ®Google Scholar

Rozycki M, Bialik JF, Speight P, et al. Myocardin-related transcription factor regulates nox4 protein expression: linking cytoskeletal organization to redox state. J Biol Chem. 2016;291(1):227–243. doi:10.1074/jbc.M115.674606

 PubMed Web of Science ®Google Scholar

Tarangelo A, Magtanong L, Bieging-Rolett KT, et al. P53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 2018;22(3):569–575. doi:10.1016/j.celrep.2017.12.077

 PubMed Web of Science ®Google Scholar

Xie Y, Zhu S, Song X, et al. The tumor suppressor p53 limits ferroptosis by blocking dpp4 activity. Cell Rep. 2017;20(7):1692–1704. doi:10.1016/j.celrep.2017.07.055

 PubMed Web of Science ®Google Scholar

Cheng H, Wang P, Wang N, et al. Neuroprotection of nrf2 against ferroptosis after traumatic brain injury in mice. Antioxidants. 2023;12(3):731. doi:10.3390/antiox12030731

 Web of Science ®Google Scholar

Dong H, Xia Y, Jin S, et al. Nrf2 attenuates ferroptosis-mediated iir-ali by modulating tert and slc7a11. Cell Death Dis. 2021;12(11):1027. doi:10.1038/s41419-021-04307-1

 PubMed Web of Science ®Google Scholar

Dang R, Wang M, Li X, et al. Edaravone ameliorates depressive and anxiety-like behaviors via sirt1/nrf2/ho-1/gpx4 pathway. J Neuroinflammation. 2022;19(1):41. doi:10.1186/s12974-022-02400-6

 PubMed Web of Science ®Google Scholar

Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of nrf2/ho-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73(17):3221–3247. doi:10.1007/s00018-016-2223-0

 PubMed Web of Science ®Google Scholar

Wang X, Chen X, Zhou W, et al. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B. 2022;12(2):708–722. doi:10.1016/j.apsb.2021.10.005

 PubMed Web of Science ®Google Scholar

Lu Q, Yang L, Xiao JJ, et al. Empagliflozin attenuates the renal tubular ferroptosis in diabetic kidney disease through AMPK/NRF2 pathway. Free Radic Biol Med. 2023;195:89–102. doi:10.1016/j.freeradbiomed.2022.12.088

 PubMed Web of Science ®Google Scholar

Hunkeler M, Hagmann A, Stuttfeld E, et al. Structural basis for regulation of human acetyl-coa carboxylase. Nature. 2018;558(7710):470–474. doi:10.1038/s41586-018-0201-4

 PubMed Web of Science ®Google Scholar

Chen H, Qi Q, Wu N, et al. Aspirin promotes RSL3-induced ferroptosis by suppressing mTOR/SREBP-1/SCD1-mediated lipogenesis in PIK3CA-mutant colorectal cancer. Redox Biol. 2022;55:102426. doi:10.1016/j.redox.2022.102426

 PubMed Web of Science ®Google Scholar

Zhang Y, Swanda RV, Nie L, et al. Mtorc1 couples cyst(e)ine availability with gpx4 protein synthesis and ferroptosis regulation. Nat Commun. 2021;12(1):1589. doi:10.1038/s41467-021-21841-w

 PubMed Web of Science ®Google Scholar