Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects

Abstract

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

Fig. 1

The important milestone of iron metabolism and ferroptosis in the muscular system. The figure presents a timeline highlighting significant milestones in the study of iron metabolism and ferroptosis in the muscular system from 1961 to 2024, including the influence of iron metabolism on muscle function, and the regulation of antioxidant system and lipid metabolism on muscle ferroptosis. This figure was created with BioRender (https://biorender.com/)

Fig. 2

Overview the mechanisms underlying ferroptosis in skeletal, cardiac, and smooth muscle. Iron overload is one of the principal driving factors of ferroptosis. Many aspects of iron metabolism such as the iron absorption, storage, and utilization are involved in regulating ferroptosis. When cellular iron is sufficient, transferrin-bound iron is reduced in order to limit excess iron accumulation. However, under iron-overload conditions, the uptake of non-transferrin-bound iron increases, facilitated by metal transporter proteins such as SLC39A14. In general, excess iron is stored in ferritin-bound substances or in the labile iron pool (LIP), which can increase due to a metabolic imbalance. Iron in the LIP participates in the production of reactive oxygen species (ROS) via the Fenton reaction. NCOA4 is a cargo receptor that binds ferritin, transporting it to autolysosomes, leading to the release of free iron. The classic intracellular pathway for inhibiting ferroptosis involves the uptake of cystine through the cystine-glutamate transporter (system Xc⁻), which results in the biosynthesis of GSH. GPX4 reduces phospholipid hydroperoxide, using GSH as a cofactor. FSP1 also reduces CoQ10 and inhibits the oxidation of phospholipids. In addition, activation of ACSL4, LPCAT3, and LOXs plays a role in ferroptosis by promoting lipid peroxidation. This figure was created with BioRender (https://biorender.com/). Abbreviations: ACSL4 acyl-CoA synthetase long-chain family member 4, DMT1 divalent metal transporter1, FPN ferroportin, FSP1 ferroptosis suppressor protein 1, GPX4 glutathione peroxidase 4, GSH glutathione, HO-1 heme oxygenase 1, LIP labile iron pool, LOXs lipoxygenases, LPCAT3 lysophospholipid acyltransferase 3, NCOA4 nuclear receptor coactivator 4, PUFA polyunsaturated fatty acid, RNS reactive nitrogen species, ROS reactive oxygen species, SLC39A14 (ZIP14) Zrt and IRT-like protein 14, STEAP3 six transmembrane epithelial antigen of prostate 3, TF transferrin, TfR1 transferrin receptor protein 1

Fig. 3

Summary of the signaling pathways that regulate ferroptosis in muscle cells. Several transcription factors such as p53, Nrf2, ATF3, and YAP regulate the transcription of ferroptosis-related genes. Noncoding RNAs are also involved in the posttranscriptional regulation of ferroptosis-related genes, affecting their expression. Acetylation and phosphorylation of Nrf2 regulate its nuclear translocation, thereby regulating the expression of downstream target genes such as SLC7A11, GPX4, and FPN. This figure was created with BioRender (https://biorender.com/). Abbreviations: ACSL4 acyl-CoA synthetase long-chain family member 4, ARE antioxidant response element, ATF3 activating transcription factor 3, BACH1 BTB domain and CNC homolog 1, CBS Cystathionine β-synthase, CDKN1A cyclin-dependent kinase inhibitor p21, DPP4 dipeptidyl peptidase 4, FPN ferroportin, GLS2 glutaminase 2, GPX4 glutathione peroxidase 4, GSH glutathione, HO-1 heme oxygenase 1, Keap1 Kelch-like ECH-associated protein 1, LIP labile iron pool, NOX NADPH oxidase, Nrf2 nuclear factor erythroid 2-related factor 2, SAT1 spermidine/spermine N1-acetyltransferase 1, Sirt2 Sirtuin-2, SLC7A11 solute carrier family 7 member 11, TF transferrin, TfR1 transferrin receptor protein 1

Fig. 4

Strategies for targeting ferroptosis in treating muscle diseases and disorders. Dysregulated iron metabolism, lipid peroxidation, oxidation, and antioxidant imbalances have all been implicated in the development of a variety of diseases and disorders affecting muscles. These muscle diseases and disorders can be treated using either inhibitors (anti-ferroptosis strategies) or inducers (pro-ferroptosis strategies). This figure was created with BioRender (https://biorender.com/). Abbreviations: 4-HNE 4-hydroxynonaldehyde, ACSL4 acyl-CoA synthetase long-chain family member 4, DFO deferoxamine, DFP Deferiprone, Fer-1 ferrostatin-1, FSP1 ferroptosis suppressor protein 1, FTH ferritin heavy chain, GPX4 glutathione peroxidase 4, GSH glutathione, HO-1 heme oxygenase-1,IRP1/2 iron-regulated protein 1/2, Lip-1 liproxstatin-1, MDA malondialdehyde, NAC N-acetylcysteine, Nrf2 nuclear factor erythroid 2-related factor 2, PTGS2 prostaglandin-endoperoxide synthase 2, ROS reactive oxygen species, SLC7A11 solute carrier family 7 member 11, SLC39A14 metal cation symporter ZIP14, SOD superoxide dismutase, TfR1 transferrin receptor protein 1