ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1660034
This article is part of the Research TopicCommunity Series in Post-Translational Modifications of Proteins in Cancer Immunity and Immunotherapy, Volume IVView all 6 articles
FBXO2 promotes hepatocellular carcinoma progression and sorafenib resistance by targeting USP49 for proteasomal degradation
Provisionally accepted
- 1Zhejiang Chinese Medical University, Hangzhou, China
- 2First Hospital of Jiaxing, Jiaxing, China
- 3Beijing Zhongwei Research Center, Beijing, China
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Introduction: Hepatocellular carcinoma (HCC) is a highly prevalent and lethal malignancy with limited treatment efficacy due to tumor heterogeneity and the development of drug resistance. Identifying novel molecular mechanisms that drive HCC progression and therapeutic resistance is critical. F-box only protein 2 (FBXO2), an E3 ubiquitin ligase, has recently been implicated in tumorigenesis. However, its role in HCC remains unclear. Methods: We employed CCK-8, EdU, Transwell, and wound healing assays to evaluate the functional role of FBXO2 in HCC cells. Furthermore, Western blotting, immunoprecipitation, in vivo ubiquitination assays, and cycloheximide chase analysis were conducted to investigate the molecular mechanisms through which FBXO2 contributes to tumor progression in HCC. Results: FBXO2 is significantly upregulated in HCC tissues and correlates with poor patient prognosis. Functional assays demonstrated that FBXO2 promotes HCC cell proliferation, migration, and invasion in vitro, while its silencing exerts tumor-suppressive effects. Mechanistically, FBXO2 directly binds to and targets the USP49 for ubiquitin-mediated proteasomal degradation. This degradation decreases USP49 stability and function, thereby enhancing oncogenic potential. Importantly, silencing USP49 reversed the inhibitory effects of FBXO2 knockdown, confirming the FBXO2/USP49 axis as a functional regulator of HCC aggressiveness. Furthermore, FBXO2 depletion significantly enhanced the sensitivity of HCC cells and xenograft tumors to sorafenib treatment. Conclusion: Collectively, our findings establish FBXO2 as a critical modulator of HCC progression and therapeutic resistance via USP49 degradation, highlighting FBXO2 as a promising therapeutic target for overcoming sorafenib resistance in HCC.
Keywords: Fbxo2, USP49, proliferation, Sorafenib, Resistance
Received: 05 Jul 2025; Accepted: 29 Aug 2025.
Copyright: © 2025 Hang, Wang, Zhang, Dong, Hu, Wang and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Peter Wang, Beijing Zhongwei Research Center, Beijing, China
Liu Xu, First Hospital of Jiaxing, Jiaxing, China
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