Geraniol inhibits the M1 polarization of Kupffer cells through PPARγ-mediated regulation of the NCoR/HDAC3/TBL1 complex and protects against acute liver failure

Background and aims Acute liver failure (ALF) is a life-threatening hepatic disorder characterized by severely impaired liver function. It is always complicated by multi-organ dysfunction and increases the risk of progressive liver failure. Our previous study revealed that geraniol exerts therapeutic effects on ALF. Therefore, this study aimed to elucidate the molecular mechanisms through which geraniol protects against ALF. Methods Kupffer cells (KCs) were isolated and treated with geraniol. PPARγ inhibitors were used to treat KCs that underwent TNF-α-induced M1 polarization or IL-4-induced M2 polarization and then were treated with geraniol. Flow cytometry was used to detect the proportion of M1 and M2 KCs. The levels of PPARγ, the NCoR complex, and their binding were measured using qPCR, Western blotting (WB), and immunoprecipitation. The effects of geraniol on ALF and KC polarization were validated in vivo. Results Geraniol inhibited the M1 polarization of KCs and promoted the induction of KCs to the M2 phenotype, thereby suppressing the secretion of pro-inflammatory factors and enhancing the secretion of anti-inflammatory factors. Treatment with PPARγ inhibited geraniol-mediated M2 polarization of KCs. On the other hand, geraniol inhibited M2-to-M1 shift of KCs induced by a PPARγ inhibitor. In vivo experiments confirmed that geraniol restored ALF pathology. Specifically, PPARγ bound to the NCoR/HDAC3/TBL1 complex and regulated KC polarization. Conclusions Geraniol regulated the polarization of hepatic KCs toward the M2 phenotype through the PPARγ-regulated NCoR complex pathway, suppressed the release of inflammatory factors, and enhanced its preventive effect on liver injury.