PSMD11 promotes hepatocellular carcinoma progression by reprogramming lipid metabolism via SREBP1/2 and PPAR-γ.
7 affiliations
- 1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 2Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
- 3State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
- 4State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
- 5State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
- 6Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China. [email protected].
- 7The Key Laboratory of Molecular Pathology (Hepatobiliary Diseases) of Guangxi, Baise, China. [email protected].
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.
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BibTeX
@article{huang2026psmd11,
title = {{PSMD11 promotes hepatocellular carcinoma progression by reprogramming lipid metabolism via SREBP1/2 and PPAR-γ.}},
author = {Zhihong Huang and Canxue Zhang and Chi Zhang and Yuqi Liu and Chao Ge and Zhujun Wei and Li Zhang and Yue Yang and Wei Tian and Hua Tian},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09175-1},
url = {https://europepmc.org/article/MED/42963355},
note = {CC BY},
}
RIS
TY - JOUR
TI - PSMD11 promotes hepatocellular carcinoma progression by reprogramming lipid metabolism via SREBP1/2 and PPAR-γ.
AU - Zhihong Huang
AU - Canxue Zhang
AU - Chi Zhang
AU - Yuqi Liu
AU - Chao Ge
AU - Zhujun Wei
AU - Li Zhang
AU - Yue Yang
AU - Wei Tian
AU - Hua Tian
PY - 2026
DA - 2026/08/18
JO - Cell death & disease
DO - 10.1038/s41419-026-09175-1
UR - https://europepmc.org/article/MED/42963355
AB - 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.
SN - 2041-4889
ER -