2. Academic Validation
  3. Stabilization of FASN by USP5-mediated deubiquitination promotes hepatocellular carcinoma progression

Stabilization of FASN by USP5-mediated deubiquitination promotes hepatocellular carcinoma progression

  • Oncogenesis. 2025 Nov 28;14(1):46. doi: 10.1038/s41389-025-00589-8.
Qinliang Fang # 1,  Changhong Luo # 1,  Yuyan Lu # 2 3,  Xijun Chen 1 4,  Ping Zhan 2,  Qin Yao 5,  Huita Wu 6 7,  Fuqiang Wang 8,  Zhenyu Yin 9,  Chengrong Xie 10
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 2 Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 3 CDL Research, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 4 Department of Hepatobiliary Surgery, Xiamen Key Laboratory of Liver Diseases, Xiamen Hospital of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Xiamen, China.
  • 5 Central Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 6 Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • 7 School of Clinial Medicine, Fujian Medical University, Fuzhou, China. [email protected].
  • 8 Department of Hepatobiliary Surgery, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • 9 Department of Hepatobiliary Surgery, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • 10 Department of Hepatobiliary Surgery, Xiamen Translational Medical Key Laboratory of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • # Contributed equally.
PMID: 41315248 DOI: 10.1038/s41389-025-00589-8
Abstract

The deubiquitinating enzyme Ubiquitin specific peptidase 5 (USP5) has attracted substantial notice for its vital role in Cancer progression. However, the USP5-mediated deubiquitination of corresponding protein substrates and its functional role in hepatocellular carcinoma (HCC) have not been fully investigated. Here, we demonstrated that USP5 expression was significantly elevated in HCC tissues. The overexpression of USP5 was closely associated with larger tumor sizes, more satellite nodules and tumor emboli, and predicted unfavorable clinical outcome in HCC patients as well. Functionally, USP5 facilitated cell proliferation, migration, and invasion, and induced lipid accumulation in vitro, along with enhanced tumor growth in vivo. Moreover, knockdown of USP5 expression showed a profound effect on lipidomic profiling, specially reduced the content of palmitic acid (PA). Treatment of PA could partially rescue the suppression of HCC mediated by USP5 knockdown. Further mechanistic investigation uncovered that Fatty acid synthase (FASN), the crucial enzyme catalyzing PA synthesis, was a downstream target of USP5. USP5 interacted with FASN, repressing the ubiquitination modification of FASN and preventing its degradation. Notably, the positive correlation between USP5 and FASN expression in HCC tissues was observed, and USP5 exerted oncogenic effects partly via FASN. Our findings revealed that USP5 promotes HCC progression through deubiquitinating FASN, and targeting the USP5-FASN-PA axis could potentially serve as a strategic approach for the therapy of HCC.

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