Cyclovirobuxine D suppresses gastric cancer growth by targeting the V-ATPase complex and inducing excessive endo-lysophagy

Gastric cancer is one of the most malignant cancers in the world, posing a significant threat to human life and persisting as a major clinical challenge. Cyclovirobuxine D (CVB-D), derived from boxwood and traditionally employed in cardiovascular disease treatment, has emerged as a promising candidate for cancer therapy. However, its mechanism of action still needs to be clearly defined. We aimed to comprehensively evaluate CVB-D's impact on gastric cancer and elucidate its underlying mechanisms. Here, we found CVB-D induced excessive endo-lysophagy in gastric cancer. Moreover, multi-omics analysis revealed that CVB-D directly engages the ATP6V0A1-containing V-ATPase complex and perturbs endo-lysosomal homeostasis, leading to abnormal lysosomal acidification, impaired lysosomal protease activity, and autophagic flux blockade. Mechanistically, damaged endo-lysosomes recruited the autophagic adaptor P62/SQSTM1 in a galectin-8-dependent manner, ultimately triggering endoplasmic reticulum (ER) stress and apoptosis in gastric cancer cells. Furthermore, through cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models, we validated the therapeutic efficacy of CVB-D against gastric cancer. Notably, CVB-D enhances the sensitivity of gastric cancer to the chemotherapeutic agent cisplatin. Our findings suggest that CVB-D holds promise as an effective therapeutic agent for gastric cancer treatment.