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

ABSTRACT 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 m 6 A‐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.