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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\u03b1-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1\u03b1 is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1\u03b1 as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1\u03b1 RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.<\/jats:p>","DOI":"10.1084\/jem.20231395","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T02:21:08Z","timestamp":1712110868000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Hepatic IRE1\u03b1-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy"],"prefix":"10.1084","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4719-5099","authenticated-orcid":true,"given":"Yuexiao","family":"Tang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00a2xv884","id-type":"ROR","asserted-by":"publisher"}],"name":"Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated 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