Hepatic regulator of G protein signaling 14 ameliorates NAFLD through activating cAMP-AMPK signaling by targeting Giα1/3

•Hepatocyte RGS14 protects against hepatic steatosis during the progression of NAFLD.•RGS14 depends on GDI activity to ameliorate HFHC-induced NASH.•RGS14-Giα1/3 interaction promoted cAMP levels, then activated AMPK signaling pathway.•Targeting RGS14 or modulating the RGS14-Giα1/3 interaction may be a potential strategy to protect against NAFLD.