胃癌是世界范围内死亡率较高的癌症。化疗耐药是胃癌治疗的障碍。已观察到线粒体功能障碍会促进恶性进展。然而，其根本机制仍不清楚。线粒体因子生长分化因子 15 (GDF15) 是线粒体疾病的重要生物标志物，由综合应激反应 (ISR) 途径激活。研究发现血清GDF15水平与胃癌患者的不良预后相关。在这项研究中，我们发现 GDF15 蛋白高表达可能会增加辅助化疗治疗的胃癌患者的疾病复发。此外，线粒体抑制剂，特别是寡霉素（一种复合物 V 抑制剂）和 salubrinal（一种 ISR 激活剂）治疗，分别被发现可以上调 GDF15 并增强人胃癌细胞的顺铂不敏感性。从机制上讲，我们发现激活转录因子 4 (ATF4)-C/EBP 同源蛋白 (CHOP) 途径在 GDF15 的增强表现中具有至关重要的功能。此外，活性氧 (ROS) 激活的一般控制非阻抑物 2 (GCN2) 介导寡霉素诱导的 ISR，并上调 GDF15。 GDF15-胶质细胞源性神经营养因子家族受体 a 样 (GFRAL)-ISR-胱氨酸/谷氨酸转运蛋白 (xCT) 增强的谷胱甘肽产生被发现与顺铂耐药有关。这些结果表明线粒体功能障碍可能通过GDF15上调增强顺铂不敏感性，而靶向线粒体因子GDF15-ISR调节可能是对抗胃癌顺铂耐药的策略。本文受版权保护。版权所有。

Gastric neoplasm is a high-mortality cancer worldwide. Chemoresistance is the obstacle against gastric cancer treatment. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. The mitokine growth differentiation factor 15 (GDF15) is a significant biomarker for mitochondrial disorder and is activated by the integrated stress response (ISR) pathway. The serum level of GDF15 was found to be correlated with the poor prognosis of gastric cancer patients. In this study, we found that high GDF15 protein expression might increase disease recurrence in adjuvant chemotherapy-treated gastric cancer patients. Moreover, treatment with mitochondrial inhibitors, especially oligomycin (a complex V inhibitor) and salubrinal (an ISR activator), respectively, was found to upregulate GDF15 and enhance cisplatin insensitivity of human gastric cancer cells. Mechanistically, it was found that the activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) pathway has a crucial function in the heightened manifestation of GDF15. In addition, reactive oxygen species (ROS)-activated general control nonderepressible 2 (GCN2) mediates the oligomycin-induced ISR, and upregulates GDF15. The GDF15-glial cell-derived neurotrophic factor family receptor a-like (GFRAL)-ISR-cystine/glutamate transporter (xCT)-enhanced glutathione production was found to be involved in cisplatin resistance. These results suggest that mitochondrial dysfunction might enhance cisplatin insensitivity through GDF15 upregulation, and targeting mitokine GDF15-ISR regulation might be a strategy against cisplatin resistance of gastric cancer.This article is protected by copyright. All rights reserved.