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

  • Cell Metab. 2024 Nov 5;36(11):2402-2418.e10. doi: 10.1016/j.cmet.2024.09.007.
Hui Lin  1 ,  Chuanshun Ma  2 ,  Xiao Zhuang  3 ,  Shuo Liu  4 ,  Dong Liu  3 ,  Mingxiang Zhang  5 ,  Yan Lu  6 ,  Guangjian Zhou  6 ,  Chao Zhang  6 ,  Tengwei Wang  5 ,  Zihao Zhang  2 ,  Lin Lv  6 ,  Daolai Zhang  5 ,  Xiong-Zhong Ruan  7 ,  Yunfei Xu  8 ,  Renjie Chai  9 ,  Xiao Yu  10 ,  Jin-Peng Sun  11 ,  Bo Chu  12
Affiliations
  • 1. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, and New Cornerstone Science Laboratory, Shandong University, Jinan 250012, China; Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration, Jinan 250012, China.
  • 2. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
  • 3. Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 4. Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 5. School of Pharmacy, Binzhou Medical University, Yantai, China.
  • 6. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, and New Cornerstone Science Laboratory, Shandong University, Jinan 250012, China.
  • 7. Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
  • 8. Department of General Surgery, Qilu Hospital, Gheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address: [email protected].
  • 9. State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China; Department of Otolaryngology Head and Neck Surgery, Sichuan, Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, China. Electronic address: [email protected].
  • 10. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China; Shandong Key Laboratory of Mental Disorders and Intelligent Control, Shandong University, Jinan 250012, China. Electronic address: [email protected].
  • 11. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, and New Cornerstone Science Laboratory, Shandong University, Jinan 250012, China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 12. Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address: [email protected].
PMID: 39389061 DOI: 10.1016/j.cmet.2024.09.007
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.

Keywords
17α-hydroxypregnenolone; GPR56; ferroptosis; liver injury.
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