ArticleInflammation2025
Pharmacological Activation of GPR68 Attenuates Ferroptosis in Spinal Cord Ischemia/Reperfusion Injury Through PI3K/Akt-Mediated Nrf2 Antioxidant Pathway.
Article in Inflammation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Brown Adipocyte Sheets Alleviate Myocardial Ischemia-Reperfusion Injury Through NRG4-ErbB4-Dependent Ferroptosis Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The Mechanism of G Protein-Coupled Receptor Regulation of Ferroptosis in Hepatic Ischemia-Reperfusion Injury.International journal of molecular sciences · 2026Review
- E2F4 Mediates Mitophagy to Inhibit Ferroptosis in Esophageal Cancer Cells by Activating GPR176.Human mutation · 2026Article
- Protective Effect of Chinese Herbal Medicine on Cerebral Ischemia-Reperfusion Injury by Regulating Ferroptosis.Drug design, development and therapy · 2026Review
- Bitter gourd bioactive peptide alleviates neuronal ferroptosis after spinal cord ischemia-reperfusion injury, combined with emerging cell and animal models.Frontiers in nutrition · 2026Article
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Authors and funding
6 authors.
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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 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.
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