GPR132 drives macrophage M1 polarization and aggravates inflammation-associated liver injury.

Macrophage polarization plays a critical role in the pathogenesis of hepatic inflammation and injury triggered by diverse insults. However, the regulators of macrophage polarization in hepatic inflammation remain largely undefined. In this study, we reported that GPR132 activation promoted macrophage M1 polarization and suppressed macrophage M2 polarization, whereas GPR132 inhibition shifted macrophages toward an anti-inflammatory and tissue-repairing M2 phenotype. Notably, genetic deletion of Gpr132 prevented hepatic macrophage M1 polarization and markedly alleviated hepatic inflammation and injury in methionine-choline-deficient (MCD)-induced metabolic dysfunction-associated steatohepatitis (MASH), choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASH, and drug-induced liver injury (DILI). Furthermore, pharmacological inhibition of GPR132 substantially mitigated hepatic inflammation and injury in MASH and DILI. Taken together, our study identifies GPR132 as a critical regulator of macrophage polarization and highlights GPR132 as a potential target for the treatment of MASH and DILI.