Ferroptosis in Critical Illness Myopathy and Ventilator-Induced Diaphragm Dysfunction: Mechanisms, Evidence Gaps, and Translational Perspectives

Abstract

ICU-acquired weakness, lengthy mechanical ventilation, difficult weaning from respiratory support, and delayed functional recovery can be largely attributed to critical illness myopathy (CIM) and ventilator-induced diaphragm dysfunction (VIDD). Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and failure of lipid-peroxide detoxification. This narrative review critically evaluates whether ferroptosis may contribute to CIM and VIDD and distinguishes direct evidence from mechanistic extrapolation. Core ferroptosis mechanisms include expansion of the labile iron pool, NCOA4-mediated ferritinophagy, impairment of the system xc−/glutathione/glutathione peroxidase 4 (GPX4) axis, ACSL4-dependent enrichment of oxidizable polyunsaturated phospholipids, and failure of complementary antioxidant systems such as FSP1-coenzyme Q. Critical illness and mechanical ventilation generate several ferroptosis-permissive conditions, including inflammation, altered iron handling, mitochondrial dysfunction, disuse, and oxidative stress. Nevertheless, direct causal evidence in human CIM and VIDD remains insufficient, and commonly used oxidative-stress markers are not specific for ferroptosis. The strongest future studies will combine tissue-specific iron and lipid-peroxidation measures, GPX4/SLC7A11/ACSL4/NCOA4-associated signatures, objective muscle-function outcomes, multi-omics profiling, and mechanistically informative rescue experiments. Ferroptosis should therefore be regarded as an emerging and testable contributor to critical-illness-associated muscle dysfunction rather than an established dominant mechanism.