GPR30 Inhibits Neuronal Apoptosis After Subarachnoid Hemorrhage by Activating the Wnt/β-Catenin Pathway in a m6A-dependent Manner

Mol Neurobiol. 2025 Mar 25. doi: 10.1007/s12035-025-04867-9. Online ahead of print.

ABSTRACT

Neuronal apoptosis is associated with early brain injury after subarachnoid hemorrhage (SAH). In this study, the regulatory effects of GPR30 on neuronal apoptosis after SAH, METTL14 expression, and the Wnt/β-catenin pathway were investigated. SAH models were constructed in vitro in neurons and in vivo in rats. We found that the GPR30 protein was downregulated in OxyHB-stimulated neurons and SAH rat brain tissue. The GPR30 agonist G1 decreased iNOS levels and apoptosis in OxyHB-stimulated neurons. G1 increased m6A levels in OxyHB-stimulated neurons, increased the expression of METTL14 and Bcl-2, and reduced Caspase-3 and Bax levels. The GPR30 inhibitor G15 had the opposite effect as G1. METTL14 overexpression increased m6A levels in OxyHB-stimulated neurons; increased the expression of METTL14, Wnt1, β-catenin, and Bcl-2; decreased Caspase-3 and Bax levels; and inhibited apoptosis. The Wnt inhibitor IWR-1 abrogated the effects of METTL14 overexpression in OxyHB-stimulated neurons. In vivo, the results revealed that G1 decreased the mNSS, cerebral edema score, and caspase-3, IL-6, IL-1β, Bax, and p-β-catenin expression; inhibited apoptosis and nitric oxide production; and increased GPR30, IFN-γ, TGF-β1, METTL14, Wnt1, and β-catenin expression. G15 had the opposite effect of G1. METTL14 knockdown abrogated the effects of G1 in SAH model rats. Our results suggest that GPR30 inhibits neuronal apoptosis after SAH via Wnt/β-catenin pathway regulation and METTL14-mediated m6A modification, providing a new therapeutic target for SAH.

PMID:40131697 | DOI:10.1007/s12035-025-04867-9