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This study unveils a novel role of G protein-coupled receptor 68 (GPR68), a pH-sensing G protein-coupled receptor (GPCR), in mitigating ferroptosis\u2014a lipid peroxidation-driven cell death\u2014through 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 Glutathione\/ Total Glutathione (GSSG\/T-GSH) levels, alongside reduced Solute Carrier Family 7 Member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4). Pharmacological activation of GPR68 with MS48107 or the clinically approved benzodiazepine Lorazepam robustly reversed ferroptosis by enhancing Akt phosphorylation and Nrf2 nuclear translocation. Mechanistically, GPR68 siRNA or PI3K\/Akt inhibition abolished these protective effects. Crucially, Lorazepam rescued neuronal viability and suppressed ferroptosis in spinal I\/R rats, effects fully negated by the GPR68 antagonist Ogremorphin (OGM). Our findings establish GPR68 as a key ferroptosis regulator and propose repurposing Lorazepam as a therapeutic strategy for SCIRI.<\/jats:p>","DOI":"10.1007\/s10753-025-02326-0","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T21:41:48Z","timestamp":1750196508000},"page":"4289-4301","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pharmacological Activation of GPR68 Attenuates Ferroptosis in Spinal Cord Ischemia\/Reperfusion Injury Through PI3K\/Akt-Mediated Nrf2 Antioxidant Pathway"],"prefix":"10.1007","volume":"48","author":[{"given":"Ruitong","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengbo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengtao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"2326_CR1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/S0140-6736(02)07603-1","volume":"359","author":"John W McDonald","year":"2002","unstructured":"McDonald, John W., Cristina Sadowsky. 2002. 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