NUB1 Regulates Muscle Atrophy in Lung Cancer Cachexia via NF‐κB Signaling Pathway
Yuqi Han, Yaru Xia, Weiquan Li, Jiaming Wu, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Xuejiao Dong, Jiemin Li, Yu Jiao, Guixiao Huang, Xiaoping Zhang, Hongmei YangABSTRACT
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.