Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University , Hangzhou, China.
Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province , Hangzhou, China.
J Exp Med. 2024 Jul 1;221(7). doi: 10.1084/jem.20231395. Epub 2024 May 2.
Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.
铂类化疗药物可导致厌食症的发生，对癌症患者的整体健康产生不利影响。然而，由于有效的治疗策略有限，管理化疗引起的厌食症和随后的体重减轻仍然具有挑战性。生长分化因子 15（GDF15）最近在化疗引起的厌食症方面受到了极大关注。在这里，我们报告肝 GDF15 在响应顺铂和阿霉素等化疗药物调节体重方面起着至关重要的作用。顺铂和阿霉素治疗诱导肝 Gdf15 表达并升高循环 GDF15 水平，导致食欲抑制和随后的体重减轻。在机制上，化学疗法选择性激活未折叠蛋白反应 (UPR) 的肝 IRE1α-XBP1 途径可上调 Gdf15 表达。IRE1α 的遗传和药理学失活足以改善化疗引起的厌食症和体重减轻。这些结果确定了肝 IRE1α 是 GDF15 介导的厌食症的分子驱动因素，并表明阻断 IRE1α RNase 活性为缓解化疗中的不良厌食症提供了一种治疗策略。
