NUB1 Regulates Muscle Atrophy in Lung Cancer Cachexia via NF-κB Signaling Pathway

Cancer-associated cachexia (CAC) is a devastating multifactorial syndrome characterized by progressive skeletal muscle atrophy. Its mechanisms remain incompletely clarified, with limited effective therapeutic targets. NUB1, a negative regulator of ubiquitin-like proteins mediating protein degradation, has not been fully elucidated in CAC-induced muscle atrophy. Here, NUB1 was significantly upregulated in skeletal muscles of Lewis lung carcinoma (LLC) cachexia mice and C2C12 myotube atrophy models stimulated with LLC tumor-conditioned medium (LCM). Silencing NUB1 alleviated LCM-induced myotube atrophy in vitro and enhanced muscle mass, fiber cross-sectional area and function in LLC cachectic mice in vivo. Mechanistically, upregulated NUB1 recruited IκBα to bind proteasomal subunit S5a, promoting IκBα degradation, thus increasing NF-κB nuclear translocation and transcription of Atrogin1 and MuRF1. Silencing NUB1 inhibited NF-κB activation, while TNFα reversed its protective effect. These findings identified NUB1 as a novel driver of CAC-related muscle atrophy and highlighted the NUB1/IκBα/NF-κB axis as a promising therapeutic target.