VGLL4 enhances PDK4 transcription and promotes metabolic dysfunction-associated fatty liver disease.

Abstract

MAFLD is a global epidemic with a limited number of approved targeted therapies, underscoring the urgent need to define its underlying regulatory mechanisms. Here, we identify VGLL4 as a positive regulator of MAFLD progression. Hepatocyte-specific overexpression of Vgll4 induces hepatic steatosis, insulin resistance, and inflammation, whereas its knockout protects mice from HFD-induced metabolic dysfunction. Mechanistically, VGLL4 strengthens the interaction between TEAD4 and CEBPA and promotes the cooperative activation of Pdk4 expression. Functional studies identify PDK4 as a downstream effector, as its knockdown alleviates VGLL4-exacerbated hepatosteatosis in vivo. YAP attenuates this regulatory mechanism and suppresses Pdk4 transcription during hepatic steatosis. Notably, administration of Super-TDU, a peptide that disrupts the VGLL4-TEADs interaction, significantly alleviates hepatic steatosis in both HFD-fed mice and Vgll4-overexpressing mice. Our findings unveil the VGLL4-TEAD4/CEBPA-PDK4 axis as a key driver of MAFLD and demonstrate that its pharmacological blockade alleviates hepatic steatosis in model mice.