©The Author(s) 2026. Published by Baishideng Publishing Group Inc. All rights reserved.
Wogonin derivative V8 enhances bortezomib efficacy in gastric carcinoma by disrupting lysosome-mediated drug resistance
Si-Chan Li, Shun-Zi Shao, Yu-Hang Zhang, Yu Zhou, Wen-Tao Shang, Yuan Gao, Qi-Bin He, Qing-Long Guo, Chuan-Yong Guo, Xiao-Bo Zhang
Si-Chan Li, Yu-Hang Zhang, Yu Zhou, Wen-Tao Shang, Qing-Long Guo, Xiao-Bo Zhang, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu Province, China
Shun-Zi Shao, Qi-Bin He, Department of Gastroenterology, Jiangning Hospital, Nanjing Medical University, Nanjing 211199, Jiangsu Province, China
Yuan Gao, Pharmaceutical Animal Experimental Center, China Pharmaceutical University, Nanjing 211198, Jiangsu Province, China
Chuan-Yong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Nanjing Medical University, Shanghai 200072, China
Co-first authors: Si-Chan Li and Shun-Zi Shao.
Co-corresponding authors: Chuan-Yong Guo and Xiao-Bo Zhang.
Author contributions: Guo CY, Guo QL, Zhang XB contributed to conceptualization and funding acquisition; Zhou Y, Shang WT contributed to validation; Li SC, Shao SZ, Zhang YH contributed to formal analysis; Li SC, Shao SZ, Zhou Y contributed to investigation and visualization; He QB, Guo QL contributed to resources; Gao Y contributed to data curation; Li SC contributed to writing original draft; Guo CY, Zhang XB contributed to writing review and editing, and supervision; all authors have read and approved the final version to be published.
Supported by the “Double First-Class University” Project of China Pharmaceutical University, No. CPU2022PZQ11; Nanjing Medical Science and Technology Development Foundation, No. YKK24223; and Outstanding Young Teacher of Qinglan Project in Jiangsu Province.
Institutional review board statement: The patient-derived organoid study was approved by the Ethics Committee of Nanjing Jiangning Hospital (No. 2024-03-150-K01).
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Ethics Committee of China Pharmaceutical University (No. 2024-08-093).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Corresponding author: Xiao-Bo Zhang, PhD, Doctor, Jiangsu Key Laboratory of Carcinoge
nesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing 210009, Jiangsu Province, China.
xiaobozhangxibo@126.com
Received: August 21, 2025
Revised: September 17, 2025
Accepted: December 23, 2025
Published online: February 28, 2026
Processing time: 174 Days and 16.1 Hours
BACKGROUND
Bortezomib (BTZ) is ineffective in gastric carcinoma (GC) due to lysosome-mediated resistance. Wogonin derivative V8 targets lysosomes.
AIM
To address the limited efficacy of BTZ in GC and explore whether wogonin derivative V8 enhances anti-GC effects by overcoming lysosome-mediated resistance.
METHODS
In vitro experiments used four human GC cell lines (MGC-803, BGC-823, AGS, and HGC-27) to assess cell viability (cell counting kit-8), lysosomal function (LysoSensor staining), autophagy (western blotting for light chain 3/p62), and drug synergy [combination index (CI)]. Liquid chromatography/mass spectrometry measured intracellular BTZ concentration. Transcription factor EB (TFEB), a master regulator of lysosomal and autophagy genes, was investigated using small interfering RNA silencing and plasmid overexpression. In vivo efficacy/safety was tested in MGC-803 xenograft nude mice, and patient-derived tumor organoids (PDOs) validated clinical relevance.
RESULTS
BTZ was trapped in GC cell lysosomes, reducing its proteasome accessibility and inducing resistance; lysosome number correlated positively with the half-maximal inhibitory concentration of BTZ. V8 induced lysosomal damage/deacidification, increasing intracellular BTZ availability. V8 + BTZ synergistically inhibited GC cell growth (CI < 1), upregulated proteotoxic stress markers (ATF4, immunoglobulin heavy chain binding protein) and apoptotic mediators (cleaved caspase-3). TFEB knockdown enhanced V8 + BTZ cytotoxicity, whereas its overexpression reduced cell death, indicating a protective role of TFEB in gastric cancer cells. In xenografts, V8 + BTZ significantly reduced tumor volume/weight (P < 0.01) without organ toxicity. PDOs showed enhanced sensitivity to V8 + BTZ vs monotherapy.
CONCLUSION
Lysosomes mediate BTZ resistance in GC; V8 overcomes this by disrupting lysosomes, enabling BTZ to target proteasomes. V8 + BTZ is a safe, effective strategy against GC.
Core Tip: We identified lysosomal trapping as a key mechanism of bortezomib resistance (BTZ) in gastric cancer. The novel agent V8 disrupts lysosomes, releasing BTZ to enhance proteasome targeting and induce lethal proteotoxic stress. The V8-BTZ combination shows strong synergy in cells, xenografts, and patient organoids, supporting its clinical potential for overcoming resistance.
