Evodiamine alleviates cancer cachexia-induced muscle atrophy by inhibiting STAT3 signaling pathway.
TL;DR
Findings identify evodiamine (EVO) as a potential therapeutic agent for the treatment of cancer-associated cachexia through targeted inhibition of STAT3 signaling through targeted inhibition of STAT3 signaling.
Abstract
Cancer-associated cachexia (CAC) is a multifactorial syndrome characterized by progressive skeletal muscle and adipose tissue wasting, for which effective therapies remain limited. Here, we report that evodiamine (EVO), a bioactive alkaloid derived from Evodia rutaecarpa, markedly alleviates bladder cancer-associated cachexia in both in vivo and in vitro models. In T24 tumor-bearing mice, EVO significantly attenuated body weight loss and preserved skeletal muscle and fat mass without affecting primary tumor growth. In C2C12 myotubes exposed to tumor-conditioned medium, EVO dose-dependently prevented myotube atrophy and suppressed the expression of the muscle-specific ubiquitin ligases MuRF1 and Atrogin-1. Transcriptomic analysis identified the JAK-STAT pathway as a key target of EVO. Mechanistically, EVO selectively inhibited STAT3 phosphorylation at Tyr705 in cachectic muscle, accompanied by reduced expression of atrophy-related markers including Trim63 (MuRF1) and Atrogin-1, and restoration of Myosin Heavy Chain expression. Pharmacological reactivation of STAT3 by the agonist Colivelin abrogated the protective effects of EVO, confirming a STAT3-dependent mechanism. Collectively, these findings identify EVO as a potential therapeutic agent for the treatment of cancer-associated cachexia through targeted inhibition of STAT3 signaling.