Ferulic acid attenuates Sarcopenia progression by inhibiting peroxisomal ACOX1

Sarcopenia, an age-related syndrome characterized by progressive loss of skeletal muscle mass, strength, and function, is closely associated with oxidative stress, inflammation, and protein metabolism imbalance. Ferulic acid (FA), a natural antioxidant, may improve sarcopenia, but its mechanism remains unclear. Sarcopenia models were established using dexamethasone (Dex)-induced C2C12 cells and BALB/c mice. CCK-8 assay, DCFH-DA fluorescence probe, immunofluorescence, RT-qPCR, Western blot, ELISA, and enzyme activity assays were employed to evaluate FA's effects on cell viability, myotube differentiation, and inflammatory factors. The interaction protein ACOX1 were screened out and its expression and activity were analyzed. This study found that FA significantly restored Dex-induced decline in cell viability, reversed myotube atrophy (increased diameter), and reduced ubiquitin-proteasome system marker MuRF-1 expression. FA inhibited ACOX1 enzyme activity and protein expression, decreasing ROS production. In mice, FA intervention improved body weight, grip strength, and gastrocnemius cross-sectional area, suppressed E3 ubiquitin ligase MuRF-1 expression, promoted myotube differentiation marker MyoD, and reduced TNF-α/IL-6 levels through inhibiting ACOX1. In conclusion, FA mitigates peroxisomal oxidative stress by inhibiting ACOX1, reduces ROS accumulation and inflammation, and improves muscle protein metabolism imbalance, providing a novel mechanism for natural targeted therapy in sarcopenia.