Background <p>Gastric cancer is an aggressive malignancy with high metastatic potential, limiting effective treatments. Resveratrol, a natural polyphenol, exhibits anti-cancer properties by modulating mitochondrial function and inducing programmed cell death (PCD) pathways. However, its role in mitochondrial disruption and the regulation of deubiquitination remains unclear.</p> Methods <p>Clinical samples and gastric cancer cell lines were analyzed to assess USP36 and SOD2 expression. Cells were treated with resveratrol, followed by functional assays (WB, qPCR, colony formation, Transwell migration, fluorescence staining) to evaluate its effects on USP36-mediated SOD2 stabilization, mitochondrial function, autophagy, and ferroptosis. A xenograft model was used to examine in vivo tumor growth.</p> Results <p>USP36 deubiquitinates and stabilizes SOD2, thereby preserving mitochondrial integrity and facilitating tumor progression. Resveratrol disrupts this axis, reducing SOD2 stability, inducing mitochondrial dysfunction, and triggering autophagy and ferroptosis. In vitro, resveratrol significantly inhibited gastric cancer cell proliferation and migration; in vivo, it suppressed tumor growth.</p> Conclusion <p>This study identifies the USP36–SOD2 axis as a critical driver of gastric cancer progression and reveals the therapeutic potential of resveratrol in targeting this pathway. By destabilizing mitochondrial function, resveratrol induces both autophagy and ferroptosis, thereby suppressing tumor progression and offering a promising strategy to improve clinical outcomes.</p> Mini abstract <p>Resveratrol inhibits USP36-mediated stabilization of SOD2, which further induces autophagy and ferroptosis by inducing mitochondrial damage and ROS accumulation, and suppressing tumor progression in a xenograft model. These findings underscore the USP36–SOD2 axis as a potential therapeutic target and highlight the adjunctive chemotherapeutic potential of resveratrol.</p> Graphical abstract <p></p>