HSF1 modulates lipid metabolism and ferroptosis in sarcopenia: a novel diagnostic biomarker and therapeutic target

Background Sarcopenia, an age-correlated decline in skeletal muscle mass and function, has been increasingly linked to ferroptosis, which is an iron-dependent form of regulated cell death driven by lipid peroxidation. Nevertheless, the diagnostic potential and mechanistic role of ferroptosis-relevant genes (FRGs) in sarcopenia remains poorly understood. Methods We integrated bioinformatics analyses and experimental validation to identify and characterize key FRGs in sarcopenia. By employing RNA-seq data from public datasets (GSE25941 and GSE9103), we identified differentially expressed FRGs and applied weighted gene co-expression network analysis (WGCNA) and multiple machine learning algorithms (comprising LASSO, SVM, KNN, XGBoost, and NNET) to screen for diagnostic biomarkers. Results Six hub FRGs ( ACSL6 , CDKN1A , ATG4D , DECR1 , HSF1 , and MIB1 ) were identified with AUC>0.8 as robust diagnostic biomarkers, among which HSF1 exhibited the highest diagnostic value (AUC = 0.9247). Molecular docking suggested quercetin and cycloheximide as potential therapeutic agents targeting HSF1. As demonstrated by functional experiments in C2C12 myoblasts, HSF1 silencing facilitated lipid metabolism, elevated ferroptosis markers, and induced muscle atrophy, while its overexpression attenuated these effects. Conclusion Our findings not only underscore the significance of FRGs in sarcopenia pathogenesis but also highlight their potential as diagnostic markers and therapeutic targets.