PLCG1 promotes sevoflurane-induced neuronal ferroptosis by enhancing K63-linked ubiquitination and proteasomal degradation of LAMP2A.

Postoperative cognitive dysfunction is a type of cognitive impairment that occurs after surgery. Here, this experiment investigated the role of PLCG1 in sevoflurane-induced model and the molecular mechanisms underlying its regulation of ferroptosis. Single-cell RNA sequencing data and bioinformatic analyses were performed using GEO datasets (GSE196239). Mice were exposed to 2.3% sevoflurane for 2 h daily for 3 consecutive days. PLCG1 expression was up-regulation in patients exposed to sevoflurane. Specifically, blood samples from these patients exhibited elevated levels of PLCG1 mRNA. Consistently, in a mouse model of sevoflurane exposure, both mRNA and protein levels of PLCG1 were significantlyincreased in brain tissue. Single-cell RNA sequencing analysis revealed that PLCG1 was predominantly expressed in astrocytes (marked by AQP4, GFAP, LUZP2, and SLC25A28) and neurons (marked by B3GAT2, ENO2, GNG2, and SLC1A1) in sevoflurane-exposed patients. In contrast, PLCG1 expression was undetectable in B cells (CD74, CD79B, CD80, CD86), T cells (CD4, CD8B, CD69, CD247), or macrophages (CD36, CD68, CD83, CD163). In conclusion, PLCG1 drives neuronal ferroptosis in the context of sevoflurane exposure by enhancing mitochondrial oxidative stress and facilitating LAMP2A ubiquitination, thereby impairing the LAMP2A/HSPA8 pathway. These findings position PLCG1 as a promising biomarker and potential therapeutic target for monitoring and mitigating sevoflurane-induced neurotoxicity. In conclusion, PLCG1 drives neuronal in the context of sevoflurane exposure by enhancing mitochondrial oxidative stress and facilitating LAMP2A Ubiquitination, thereby impairing the LAMP2A/HSPA8 pathway. These findings position PLCG1 as a promising biomarker and potential therapeutic target for monitoring and mitigating sevoflurane-induced neurotoxicity.