Abstract
Hypopharyngeal squamous cell carcinoma (HPSCC) is a highly aggressive malignancy with a poor prognosis. This study elucidates the role of the E3 ubiquitin ligase Tripartite Motif Containing 15 (Trim15) and its substrate, mitochondrial voltage-dependent anion channel 3 (VDAC3), in regulating autophagy, mitophagy, and chemoresistance in HPSCC. We found that Trim15 is significantly downregulated in HPSCC tissues and inhibits cell proliferation and migration in FaDu and Detroit 562 cells. Trim15 stabilizes VDAC3 via K6-linked ubiquitination, thereby suppressing autophagy and mitophagy while elevating reactive oxygen species (ROS) levels. VDAC3 knockdown enhances autophagy and mitophagy, concomitantly reducing ROS and promoting cancer cell survival. High-concentration ethanol suppresses Trim15 and VDAC3 expression, suggesting an adaptive response to oxidative stress. Notably, chloroquine (CQ), an autophagy inhibitor, enhances HPSCC sensitivity to 5-fluorouracil (5-FU), with synergistic effects observed in xenograft models. These findings establish the Trim15-VDAC3-mitophagy axis as a critical regulator of HPSCC progression and chemoresistance, offering a novel therapeutic target for augmenting the efficacy of autophagy inhibitors in combination with standard chemotherapy.
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Acknowledgements
This study was supported by the Natural Science Foundation of Shandong Province (ZR2022MH073), National Natural Science Foundation of China (81672662), Qingdao Medical and Health Science and Technology Program (2021-WJZD184), and Clinical Medicine + X Scientific Research Project of Affiliated Hospital of Qingdao University (QDFY + X202101012).
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Guangyi Wang: Conceptualization; Methodology and Investigation; Formal Analysis; Writing-original draft. Yibang Shen and Lin Wang: Conceptualization; Methodology and Investigation; Fangyu Chai and Mingjin Xu: Methodology and Investigation. Yichuan Huang and Tao Fu: Resources. Yan Jiang: Conceptualization; Project administration and Funding acquisition. Jisheng Zhang: Conceptualization; Writing-review and editing and Validation; Project administration and Funding acquisition. The work reported in the article has been performed by the authors, unless clearly specified in the text. All authors approved the submitted version.
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Wang, G., Shen, Y., Wang, L. et al. Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02943-0
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DOI: https://doi.org/10.1038/s41420-026-02943-0
