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.