Sensing steroid hormone 17a-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury

被引：14

作者：

Lin, Hui ^{[1
,2
,13
,14
]}

Ma, Chuanshun ^{[4
,5
]}

Zhuang, Xiao ^{[6
]}

Liu, Shuo ^{[7
]}

Liu, Dong ^{[6
]}

Zhang, Mingxiang ^{[10
]}

Lu, Yan ^{[1
,2
,3
]}

Zhou, Guangjian ^{[1
,2
,3
]}

Zhang, Chao ^{[1
,2
,3
]}

Wang, Tengwei ^{[10
]}

Zhang, Zihao

Lv, Lin ^{[1
,2
,3
]}

Zhang, Daolai ^{[10
]}

Ruan, Xiong-Zhong ^{[19
,20
]}

Xu, Yunfei ^{[15
]}

Chai, Renjie ^{[16
,17
,18
]}

Yu, Xiao ^{[4
,5
,12
]}

Sun, Jin-Peng ^{[1
,2
,3
,8
,9
,11
]}

Chu, Bo ^{[6
]}

机构：

[1] Shandong Univ, Key Lab Expt Teratol, Minist Educ, Jinan 250012, Peoples R China

[2] Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Biochem & Mol Biol, Jinan 250012, Peoples R China

[3] Shandong Univ, New Cornerstone Sci Lab, Jinan 250012, Peoples R China

[4] Shandong Univ, Sch Basic Med Sci, Key Lab Expt Teratol, Minist Educ, Jinan 250012, Peoples R China

[5] Shandong Univ, Sch Basic Med Sci, Dept Physiol, Jinan 250012, Peoples R China

[6] Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Cell Biol, Jinan 250012, Peoples R China

[7] Shandong Univ, Dept Geriatr Med, Qilu Hosp, Jinan 250012, Peoples R China

[8] Shandong Univ, NHC Key Lab Otorhinolaryngol, Qilu Hosp, Jinan 250012, Peoples R China

[9] Shandong Univ, Adv Med Res Inst, Cheeloo Coll Med, Jinan 250012, Peoples R China

[10] Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China

[11] Peking Univ, State Key Lab Vasc Homeostasis & Remodeling, Beijing 100191, Peoples R China

[12] Shandong Univ, Key Lab Reprod Endocrinol Minist Educ, Jinan 250012, Shandong, Peoples R China

[13] Shandong Univ, Sch & Hosp Stomatol, Cheeloo Coll Med, Dept Periodontol, Jinan 250012, Peoples R China

[14] Shandong Key Lab Oral Tissue Regenerat, Jinan 250012, Peoples R China

[15] Shandong Univ, Qilu Hosp, Gheeloo Coll Med, Dept Gen Surg, Jinan 250012, Peoples R China

[16] Southeast Univ, Jiangsu Prov High Tech Key Lab Biomed Res, Dept Otolaryngol Head & Neck Surg, Sch Life Sci & Technol,Adv Inst Life & Hlth,Dept O, Nanjing 210096, Peoples R China

[17] Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong 226001, Peoples R China

[18] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Otolaryngol Head & Neck Surg, Chengdu 610000, Peoples R China

[19] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Ctr Lipid Res,Key Lab Mol Biol Infect Dis,Minist E, Chongqing 400016, Peoples R China

[20] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing 400016, Peoples R China

来源：

CELL METABOLISM | 2024年 / 36卷 / 11期

基金：

国家重点研发计划; 中国国家自然科学基金; 中国博士后科学基金;

关键词：

PROTEIN-COUPLED RECEPTOR; COMPLEX; GPCR; CELLS; GPR56/ADGRG1; GROMACS; CELSR3;

D O I：

10.1016/j.cmet.2024.09.007

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

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 17a-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.

引用

页码：2402 / 2418.e10

页数：28

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