A Sesquiterpenoid from Schizophyllum commune Protects C17.2 Neural Stem Cells Against Oxidative Stress Through Modulation of GPCR-Associated Signaling Pathways

The chemical constituents and neuroprotective potential of Schizophyllum commune remain insufficiently characterized. Therefore, we isolated and identified five secondary metabolites (A–E) from S. commune, and investigated their neuroprotective activities and underlying mechanisms. Compound C showed the most significant protective effect against H2O2-induced cytotoxicity in C17.2 neural stem cells. Spectroscopy was used to structurally characterize the isolated compounds. Using RNA sequencing (RNA-seq), compound C was found to significantly modulate genes associated with G protein-coupled receptor (GPCR)-related signaling pathways and neuroactive ligand–receptor interactions. Differentially expressed genes, including Adora2a, S1pr1, Adm, Tbxa2r, and Grin3b, were validated using quantitative real-time PCR. They are associated with GPCR-related signaling and neurotransmission pathways, consistent with the RNA-seq data. As indicated by the functional enrichment analysis, compound C may regulate neuronal stress responses through GPCR-associated signaling networks. In the Western blot, compound C markedly attenuated H2O2-induced protein kinase A (PKA) C phosphorylation without altering total PKA C expression, suggesting that modulation of the cAMP/PKA signaling pathway may contribute to the neuroprotective effects of compound C. Collectively, compound C may exert neuroprotective effects against oxidative stress-induced neuronal injury, potentially through the modulation of GPCR-mediated PKA signaling. S. commune is a promising natural bioactive compound source for further development in neuroprotective research.