Sarcopenia, the age-related loss of skeletal muscle mass and function, is a major driver of frailty in older adults, yet its molecular basis remains incompletely defined. Ferroptosis, an iron-dependent regulated cell death, has emerged as a link between iron dysregulation and muscle wasting in aging. However, ferroptosis-related signatures and their interplay with immune remodeling in degenerating muscle remain uncharacterized. DMD shares selected molecular and pathological features with aging-related muscle degeneration, including iron overload, oxidative stress, and impaired regenerative capacity, and may provide a disease-accelerated context for exploring ferroptosis-associated muscle pathology. We integrated two DMD transcriptomic datasets from GEO to identify 35 ferroptosis-related differentially expressed genes. Protein-protein interaction analysis identified three hub genes (HIF1A, CDKN1A, and CD44), which are related to hypoxic responses, cellular senescence, and iron-associated cellular processes, respectively. ROC analysis showed high internal discriminatory performance within the integrated dataset. CIBERSORT-based analysis suggested altered immune cell composition, including increased estimated proportions of γδ T cells and M2 macrophages and decreased regulatory T cells. Correlations between hub gene expression and estimated immune cell populations suggested a potential association between ferroptosis-related transcriptional changes and immune remodeling. Reverse transcription-quantitative PCR (RT-qPCR) validated the upregulation of HIF1A, CDKN1A, and CD44 mRNA, whereas western blotting (WB) confirmed significantly increased protein levels of HIF-1α and CD44 in mdx mice. These findings suggest a ferroptosis-related and immune-associated transcriptional and expression-level signature in dystrophic muscle that may be relevant to aging-related muscle degeneration and warrants further validation using direct ferroptosis assays, aged muscle models, and clinical sarcopenia cohorts.
