Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma.

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.