Pharmacological Activation of GPR68 Attenuates Ferroptosis in Spinal Cord Ischemia/Reperfusion Injury Through PI3K/Akt-Mediated Nrf2 Antioxidant Pathway.

ABSTRACT: Spinal cord ischemia-reperfusion injury (SCIRI) is a devastating condition with limited therapeutic options. This study unveils a novel role of G protein-coupled receptor 68 (GPR68), a pH-sensing G protein-coupled receptor (GPCR), in mitigating ferroptosis-a lipid peroxidation-driven cell death-through the Phosphoinositide 3-Kinase/ Protein Kinase B/ Nuclear Factor Erythroid 2-Related Factor 2 (PI3K/Akt/Nrf2) antioxidant axis. Using in vitro (Oxygen-Glucose Deprivation/Reperfusion (OGD/R)-treated Pheochromocytoma Cell Line 12 (PC12) cells ) and in vivo (rat spinal cord ischemia-reperfusion (I/R) ) models, we demonstrate that GPR68 downregulation exacerbates ferroptosis, evidenced by elevated Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), Malondialdehyde (MDA), and Oxidized Glutath

SUBMITTER: Yang R 

PROVIDER: S-EPMC12722321 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature