PSMD11 promotes hepatocellular carcinoma progression by reprogramming lipid metabolism via SREBP1/2 and PPAR-γ

Abstract Dysregulation of the ubiquitin-proteasome system (UPS) plays a pivotal role in tumor progression. PSMD11, a non-ATPase regulatory subunit of the 26S proteasome, has been implicated as an oncogenic factor in several cancer types; however, its precise biological function and molecular mechanisms in hepatocellular carcinoma (HCC) remain incompletely understood. In this study, we demonstrated that PSMD11 was markedly upregulated in HCC tissues and correlated with poor patient prognosis. Functionally, PSMD11 overexpression promoted HCC cell proliferation, migration, and invasion, whereas its knockdown exerted opposite effects. Mechanistically, we reveal that PSMD11 drives HCC progression by reprogramming lipid metabolism. We identified a novel pathway in which PSMD11 physically interacted with PSMD7 and PSMD14, leading to decreased ubiquitination of the transcription factors SREBP1/2 and PPAR-γ. Notably, PPAR-γ directly bound to the CPT1A promoter to enhance its transcription, thereby promoting fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). In conclusion, our findings uncover a PSMD11–PSMD14–SREBP1/2-PPAR-γ–CPT1A regulatory axis that orchestrates metabolic reprogramming in HCC. Targeting this signaling cascade may represent a promising therapeutic strategy for the precision treatment of HCC, particularly in tumors exhibiting UPS dysregulation.