Palmitoylation of Tfr1 enhances platelet ferroptosis and liver injury in heat stroke

作者：Qiyuan An, Riqing Wei, Zhicheng Huang, Youyong Tang, Minghao Wang, Sixiao He, Kaihua Huang, Zhifeng Liu, Meimei Zhang, Ru Li, Junhao Huang, Keying Zhang, Jingjing Ji, Liwei Xie, Qiang Ma · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.10.027 · 被引用次数：2 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、Iron Metabolism and Disorders

Heat stroke (HS) is a severe medical emergency characterized by coagulation and high mortality due to organ injury. This study identifies a novel mechanism in which platelet ferroptosis, driven by transferrin receptor 1 (Tfr1) palmitoylation, significantly contributes to liver injury in HS. Our findings reveal a strong inverse correlation between platelet count and organ damage, especially liver injury, as well as mortality rates. Using murine models, we demonstrate that inhibiting Tfr1-mediated ferroptosis in platelets mitigates thrombocytopenia and decreases Interleukin-1 β (IL-1 β ) secretion, thereby improving liver function and survival outcomes. This research highlights Tfr1 palmitoylation as a critical factor in iron transport within platelets, with the palmitoylation inhibitor 2-bromopalmitate (2BP) effectively reducing total iron, Fe 2+ , lipid ROS, 4-hydroxynonenal (4-HNE), and cell cytotoxicity under heat stress. These results suggest that targeting Tfr1 palmitoylation-dependent ferroptosis in platelets offers a novel therapeutic strategy for treating HS-induced thrombocytopenia and liver injury.