👤 Authors: Yaru Xia, Yuqi Han, Weiquan Li, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Jiaming Wu, Qianqian Luo, Jiemin Li, Pian Liu, Hongli Liu, Guixiao Huang, Xiaoping Zhang, Hongmei Yang
PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.
Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting. However, the molecular link between tumor metabolic stress and muscle degradation remains elusive.
Here, we identify phosphatidylethanolamine-binding protein 4 (PEBP4) as a key regulator of muscle homeostasis under cachectic conditions. PEBP4 expression is markedly suppressed in lung cachectic models and is inversely correlated with tumor-derived lactate levels.
Mechanistically, PEBP4 stabilizes NRF2 by competitively binding to KEAP1, enhancing antioxidant defense, inhibiting NF-κB signaling, and downregulating muscle atrophy-related genes MuRF1 and Fbxo32 (also known as Atrogin-1). In vitro and in vivo overexpression of PEBP4 mitigates oxidative stress, preserves muscle mass, and improves strength and endurance in Lewis lung carcinoma tumor-bearing mice.
These protective effects are significantly attenuated by NRF2 inhibition, highlighting its critical role in PEBP4-mediated signaling. Collectively, our findings uncover a tumor lactate-PEBP4-NRF2 axis linking cancer metabolism to redox imbalance and muscle wasting, and suggest the therapeutic potential of targeting the PEBP4-NRF2 pathway in lung cancer-associated cachexia.
