In parallel with the NAFLD/NASH models in vivo, we observed that E2-mediated activation of AMPK signaling and inhibition of NF-κB signaling was completely dispelled in primary hepatocytes from the GPER1-HKO female mice, GPER1 KO L02 cells, and GPER1 KO HepG2 cells under PO stimulation (Fig. S11). Here, PRKAA2 is linked to metabolic dysfunction-associated steatotic liver disease.