The significant improvement in NAFLD progression detected in HIF-2α-deleted mice was related to a selective downregulation of the expression of histidine-rich glycoprotein (HRGP), a pro-inflammatory cytokine expressed by hepatocytes (i.e., a hepatokine) that was previously shown to be upregulated in both NAFLD and chronic hepatitis C patients and able to sustain M1 macrophage polarization and CLD progression [127]. Here, HRG is linked to metabolic dysfunction-associated steatotic liver disease.