USP47 stabilizes HDAC2 to ameliorate cigarette smoke-induced skeletal muscle atrophy by suppressing CYP1A1/ROS-mediated autophagy.

Skeletal muscle atrophy, a debilitating complication of COPD, is closely linked to cigarette smoke (CS) exposure. The epigenetic regulator HDAC2 has been implicated, but the upstream regulatory mechanisms and precise downstream pathways are unclear. Using a CS-induced mouse atrophy model and C2C12 myotubes treated with cigarette smoke extract (CSE), we systematically investigated the role of USP47/HDAC2/CYP1A1/ROS axis through gain/loss-of-function studies, RNA-seq, ChIP-qPCR, co-immunoprecipitation, and ubiquitination assays. HDAC2 was downregulated in atrophic muscle, and its overexpression mitigated CS-induced atrophy, improved grip strength, and enhanced muscle regeneration. HDAC2 acted as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the promoter, thus curtailing ROS-driven excessive autophagy. We further discovered that the deubiquitinase USP47 is the key upstream regulator of HDAC2. USP47 directly interacted with HDAC2, promoted its deubiquitination, and enhanced its protein stability. Consequently, USP47 overexpression phenocopied the benefits of HDAC2 overexpression, which were effectively nullified by restoring CYP1A1 expression. In conclusion, we delineate a previously unrecognized signaling axis wherein USP47 stabilizes HDAC2 to inhibit the CYP1A1/ROS/autophagy cascade, ultimately protecting against CS-induced skeletal muscle atrophy. Targeting the USP47-HDAC2 interface presents a novel therapeutic strategy for combating muscle wasting in COPD.