Irisin Regulates Microglia M1/M2 Polarization and Promotes Autophagy Through the Sirt3 Pathway to Alleviate POCD

Cognitive impairment following surgical procedures, termed postoperative cognitive dysfunction (POCD), is a significant complication affecting the central nervous system. This condition stems from the combined impacts of anesthesia and surgical intervention, with microglial-induced neuroinflammation identified as the primary pathological mechanism. Irisin, a recently identified hormone released during physical exercise, has shown remarkable anti-inflammatory and neuroprotective properties, largely through its ability to modulate microglial activation in various central nervous system disorders. In this study, we explored the protective effects of irisin and its underlying mechanisms in a mouse model of POCD and BV2 microglial cells. Our results demonstrated that irisin effectively mitigated hippocampal-dependent cognitive deficits in mice subjected to exploratory laparotomy. Additionally, irisin facilitated the phenotypic shift of microglia from the pro-inflammatory M1 state to the anti-inflammatory and reparative M2 state. Furthermore, irisin upregulated the expression of Sirt3 in the postoperative hippocampus of mice. Importantly, pharmacological inhibition of Sirt3 activity using 3-TYP nullified the neuroprotective effects of irisin. In vitro studies revealed that irisin increased the expression of Sirt3 and autophagy-related proteins in lipopolysaccharide-activated BV2 microglial cells. Notably, Sirt3 knockout impeded irisin-induced autophagy enhancement and inhibited the polarization of microglia toward the M2 phenotype. Collectively, these findings highlight irisin’s ability to attenuate POCD by driving the phenotypic transition of microglia from M1 to M2 through a mechanism involving Sirt3-mediated autophagy. This novel pathway underscores the therapeutic potential of irisin as a promising candidate for managing POCD. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.