Targeting VPS35 increases chemotherapy sensitivity in gastric cancer cells via regulation of the NF-κB signaling pathway.

Vacuolar protein sorting-associated protein 35 (VPS35), a core component of the retromer complex, recognizes cytosolic retrieval signals in cargo proteins and mediates intracellular protein transport. Although previous studies have demonstrated that VPS35 promotes the growth and invasion of gastric cancer (GC), its role and mechanisms in GC chemoresistance remain largely uncharacterized. Here, VPS35 is identified as a potential predictive biomarker for chemotherapy response in GC. Clinically relevant chemotherapeutic agents, including 5-fluorouracil and cisplatin, significantly upregulate VPS35 expression, which is inversely associated with chemosensitivity. Functional assays demonstrate that VPS35 overexpression induces chemoresistance in GC cells, whereas VPS35 knockdown enhances tumor sensitivity to drug-induced cytotoxicity. Mechanistically, VPS35 contributes to chemoresistance by facilitating the nuclear translocation of p65 and activating the NF-κB signaling pathway. These findings suggest that VPS35 may serve as a prognostic biomarker and a promising therapeutic target in GC.