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

VGLL4 promotes MAFLD progression by enhancing PDK4 transcription, with hepatocyte-specific overexpression inducing steatosis and knockout protecting mice from metabolic dysfunction.

• Why it matters: MAFLD lacks targeted therapies and its regulatory mechanisms are not fully understood, highlighting the need to identify key molecular drivers of disease progression.
• What they did: The study used hepatocyte-specific Vgll4 overexpression and knockout mice, along with molecular analyses, to demonstrate VGLL4’s role in activating Pdk4 via TEAD4 and CEBPA interactions, and tested a peptide disruptor.
• The result: Disrupting VGLL4-TEAD interactions with Super-TDU alleviated hepatic steatosis, suggesting that targeting the VGLL4-TEAD4/CEBPA-PDK4 axis could be a therapeutic strategy for MAFLD.