Resveratrol targets mitochondrial USP36-SOD2 to induce autophagy-ferroptosis and inhibit gastric cancer progression.

IF 5.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Gastric Cancer Pub Date : 2025-07-12 DOI:10.1007/s10120-025-01645-3

Xuan Zhao, Sheng Lu, Min Yan, Zheng-Gang Zhu, Feng Dong, Chao Yan

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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. 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.

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白藜芦醇靶向线粒体USP36-SOD2诱导自噬-铁下垂，抑制胃癌进展。

背景：胃癌是一种具有高转移潜力的侵袭性恶性肿瘤，限制了有效的治疗。白藜芦醇是一种天然多酚，通过调节线粒体功能和诱导程序性细胞死亡（PCD）途径表现出抗癌特性。然而，其在线粒体破坏和去泛素化调控中的作用尚不清楚。方法：采用临床标本和胃癌细胞系检测USP36和SOD2的表达。用白藜芦醇处理细胞，然后进行功能分析（WB、qPCR、菌落形成、Transwell迁移、荧光染色），以评估其对usp36介导的SOD2稳定、线粒体功能、自噬和铁凋亡的影响。采用异种移植瘤模型观察肿瘤在体内的生长情况。结果：USP36去泛素化并稳定SOD2，从而保持线粒体完整性并促进肿瘤进展。白藜芦醇破坏这条轴，降低SOD2的稳定性，诱导线粒体功能障碍，并引发自噬和铁下垂。在体外，白藜芦醇显著抑制胃癌细胞的增殖和迁移；在体内，它抑制肿瘤生长。结论：本研究确定了USP36-SOD2轴是胃癌进展的关键驱动因素，并揭示了白藜芦醇靶向该通路的治疗潜力。通过破坏线粒体功能，白藜芦醇诱导自噬和铁下垂，从而抑制肿瘤进展，为改善临床结果提供了一个有希望的策略。在异种移植物模型中，白藜芦醇抑制usp36介导的SOD2稳定化，通过诱导线粒体损伤和ROS积累进一步诱导自噬和铁凋亡，并抑制肿瘤进展。这些发现强调了USP36-SOD2轴作为一个潜在的治疗靶点，并强调了白藜芦醇的辅助化疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gastric Cancer 医学-胃肠肝病学

CiteScore

14.70

自引率

2.70%

发文量

审稿时长

6-12 weeks

期刊介绍： Gastric Cancer is an esteemed global forum that focuses on various aspects of gastric cancer research, treatment, and biology worldwide. The journal promotes a diverse range of content, including original articles, case reports, short communications, and technical notes. It also welcomes Letters to the Editor discussing published articles or sharing viewpoints on gastric cancer topics. Review articles are predominantly sought after by the Editor, ensuring comprehensive coverage of the field. With a dedicated and knowledgeable editorial team, the journal is committed to providing exceptional support and ensuring high levels of author satisfaction. In fact, over 90% of published authors have expressed their intent to publish again in our esteemed journal.