Ferroptosis as a Nexus in Skeletal Muscle Pathophysiology: From Molecular Networks to Precision Medicine

Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is a central pathological mechanism unifying diverse skeletal muscle disorders, including atrophy (e.g., sarcopenia, CKD), impaired regeneration, and acute injury. This review synthesizes recent evidence to map a multilayered regulatory network encompassing dysregulated iron/lipid metabolism, collapsed antioxidant defenses (e.g., GPX4, FSP1, GCH1), organelle cross-talk, and complex signaling pathways (e.g., NRF2, p53). Critical translational gaps persist, such as a lack of human validation, insufficient understanding of context-dependent regulation, and challenges in biomarker development. Future directions must prioritize human biomarker discovery, elucidate nonautonomous drivers (e.g., senescent macrophages), evaluate organelle-targeted therapies, and advance biomarker-stratified trials with repurposed drugs (e.g., SGLT2 inhibitors) to enable ferroptosis-targeted precision medicine for muscle diseases.