Cyclovirobuxine D suppresses gastric cancer growth by targeting the V-ATPase complex and inducing excessive endo-lysophagy
- 1State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400716, China
- 2Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
Abstract
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, subsequent experimental analyses revealed that CVB-D directly engages the ATPase H+ transporting V0 subunit a1 (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/sequestosome 1 (SQSTM1) in a galectin8 (Gal8)-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.
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BibTeX
@article{li2026cyclovirobuxine,
title = {{Cyclovirobuxine D suppresses gastric cancer growth by targeting the V-ATPase complex and inducing excessive endo-lysophagy}},
author = {Chongyang Li and Minghao Xu and Yacong Ji and Chaowei Deng and Sicheng Wan and Xiangfei Ding and Kui Zhang and Erhu Zhao and Guangzhao Pan and Xin Hu and Changhong Li and Haoyan Ji and Xiaosong Hu and Shaomin Shi and Hongjuan Cui},
journal = {Journal of pharmaceutical analysis},
year = {2026},
month = may,
doi = {10.1016/j.jpha.2026.101672},
url = {https://europepmc.org/article/PMC/PMC13742328},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Cyclovirobuxine D suppresses gastric cancer growth by targeting the V-ATPase complex and inducing excessive endo-lysophagy
AU - Chongyang Li
AU - Minghao Xu
AU - Yacong Ji
AU - Chaowei Deng
AU - Sicheng Wan
AU - Xiangfei Ding
AU - Kui Zhang
AU - Erhu Zhao
AU - Guangzhao Pan
AU - Xin Hu
AU - Changhong Li
AU - Haoyan Ji
AU - Xiaosong Hu
AU - Shaomin Shi
AU - Hongjuan Cui
PY - 2026
DA - 2026/05/26
JO - Journal of pharmaceutical analysis
DO - 10.1016/j.jpha.2026.101672
UR - https://europepmc.org/article/PMC/PMC13742328
AB - 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, subsequent experimental analyses revealed that CVB-D directly engages the ATPase H+ transporting V0 subunit a1 (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/sequestosome 1 (SQSTM1) in a galectin8 (Gal8)-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.
SN - 2095-1779
SN - 2214-0883
ER -