山东大学初波等研究人员合作发现，GPR56感知类固醇激素17α-羟孕烯醇酮保护肝脏免受铁死亡引起的损伤。相关论文于2024年10月9日在线发表于国际学术期刊《细胞—代谢》。

研究人员发现GPR56/ADGRG1使细胞对铁死亡具有抗性，且缺乏GPR56会加剧由多柔比星（DOX）或缺血再灌注（IR）引起的铁死亡介导的肝损伤。机制上，GPR56通过促进CD36的内吞-溶酶体降解，减少含有游离多不饱和脂肪酸（PUFA）的磷脂丰度。

通过筛选一系列类固醇激素，研究人员发现17α-羟孕烯醇酮（17-OH PREG）作为GPR56的激动剂，能有效对抗铁死亡，并在损伤前后显著减轻肝损伤。此外，疾病相关的GPR56突变体对17-OH PREG激活无反应，且不足以抵御铁死亡。

总之，该研究揭示了17-OH PREG-GPR56轴介导的信号传导作为一种新的抗铁死亡途径，在维持肝脏稳态中发挥作用，为肝损伤的潜在治疗提供了新的见解。

据了解，G蛋白偶联受体（GPCR）介导了大多数细胞对激素、神经递质和环境刺激的反应。然而，GPCR是否通过铁死亡参与组织稳态调节尚不清楚。

附：英文原文

Title: Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury

Author: Hui Lin, Chuanshun Ma, Xiao Zhuang, Shuo Liu, Dong Liu, Mingxiang Zhang, Yan Lu, Guangjian Zhou, Chao Zhang, Tengwei Wang, Zihao Zhang, Lin Lv, Daolai Zhang, Xiong-Zhong Ruan, Yunfei Xu, Renjie Chai, Xiao Yu, Jin-Peng Sun, Bo Chu

Issue&Volume: 2024-10-09

Abstract: 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.

DOI: 10.1016/j.cmet.2024.09.007

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00371-1