Abstract

Skeletal muscle atrophy is a complex condition associated with various diseases, including chronic inflammation, and significantly impairs quality of life. Parthenolide, a bioactive compound derived from Tanacetum parthenium (feverfew), is well known for its anti‐inflammatory properties, but its potential therapeutic effects on muscle atrophy remain underexplored. In this study, we evaluated the protective effects of parthenolide against muscle atrophy in both in vitro and in vivo models. Using TNF‐α‐treated C2C12 myotubes and a lipopolysaccharide (LPS)‐induced muscle atrophy in mice, we assessed the impact of parthenolide through histology, functional assays, and molecular analyses. Our results demonstrated that parthenolide promoted myoblast differentiation and alleviated TNF‐α‐induced myotube atrophy by restoring myosin heavy chain (MyHC) expression and inhibiting muscle‐specific ubiquitin ligases MuRF1 and MAFbx. Mechanistically, parthenolide regulates protein homeostasis by activating the Akt–mTOR pathway, inhibiting FoxO transcription factors, and suppressing inflammation via NF‐κB inhibition. In vivo, parthenolide effectively reduced LPS‐induced muscle mass loss, muscle fiber atrophy, and grip strength decline, with improvements linked to the downregulation of atrophy markers and the preservation of MyHC levels in muscle tissue. These findings indicate that parthenolide mitigates skeletal muscle atrophy through dual regulation of protein homeostasis and inflammation, highlighting its potential as a novel therapeutic agent for muscle‐wasting disorders such as sarcopenia. Parthenolide attenuates skeletal muscle atrophy through coordinated regulation of protein homeostasis and inflammatory signaling. It counteracts TNF‐α‐mediated inhibition of AKT signaling, thereby restoring AKT–mTOR activation to promote protein synthesis and suppress protein degradation throu