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Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy

Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy
Author Tang, YX; Yao, T; Tian, X; Xia, XT; Huang, XX; Qin, ZW; Shen, Z; Zhao, L; Zhao, YP; Diao, BW; Ping, Y; Zheng, XX; Xu, YH; Chen, H; Qian, T; Ma, T; Zhou, B; Xu, SW; Zhou, QM; Liu, Y; Shao, ML; Chen, W; Shan, B; Wu, Y
Journal JOURNAL OF EXPERIMENTAL MEDICINE
Pub Year 2024
Type
Abstract

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 IRE1 alpha-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1 alpha is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1 alpha as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1 alpha RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

Issue 221
Volume 221
SCI 12.6