RGS16 Aggravates Hepatic Ischemia-Reperfusion Injury via Hepatocyte-Intrinsic Apoptosis/Inflammation & Neutrophil Recruitment/NETosis.

Hepatic ischemia-reperfusion injury (HIRI) is a frequent and severe complication after liver transplantation and hepatectomy, driven by sterile inflammation and lacking effective therapies. Regulator of G-protein signaling 16 (RGS16) is an inflammatory modulator, but its role in HIRI remains unclear. We found that RGS16 expression was markedly increased in the livers of post-hepatectomy patients and positively correlated with neutrophil extracellular trap formation (NETosis). Using hepatocyte-specific Rgs16 knockout and transgenic mouse models, we demonstrated that Rgs16 deficiency attenuated hepatic inflammation and apoptosis after HIRI, whereas Rgs16 overexpression significantly exacerbated liver injury. Integrated multi-omics analyses, including RNA-seq, MeRIP-seq, and mass spectrometry, identified C-X-C motif chemokine ligand 1 (CXCL1) as a key downstream effector of RGS16. Mechanistically, RGS16 competitively binds YTH domain family protein 3 (YTHDF3), displacing poly(A)-nuclease deadenylation complex subunit 3 (PAN3) and stabilizing m6A-modified Cxcl1 mRNA, thereby enhancing CXCL1 expression. Elevated CXCL1 promotes hepatocyte apoptosis and inflammation through C-X-C chemokine receptor 2 (CXCR2) and drives neutrophil recruitment and NETosis. Pharmacological inhibition of CXCL1 or degradation of NETs with DNase I significantly alleviated RGS16-induced liver injury. Collectively, RGS16 aggravates HIRI by amplifying hepatocyte-intrinsic CXCL1-CXCR2 signaling and CXCL1-mediated neutrophil recruitment and NETosis, suggesting RGS16 and its downstream pathways as potential therapeutic targets for HIRI.