类固醇激素
激素
肝损伤
类固醇
生物
细胞生物学
癌症研究
医学
化学
内分泌学
作者
Hui‐Ming Lin,Chuanshun Ma,Xiao Zhuang,Бо Лю,Dong Liu,M. Zhang,Junxi Lu,Guangwen Zhou,Chao Zhang,T Wang,Zihao Zhang,Lin Lv,Daolai Zhang,Ruan Xue-yu,Yunfei Xu,Renjie Chai,Yao Xiao,Jin‐Peng Sun,Bo Chu
标识
DOI:10.1016/j.cmet.2024.09.007
摘要
G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.
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