Yixing Chen, Xiaodong Wang, Wentao Yu, Meixi Gong, Yi Lu, Jinjin Xu, Hao Zhang, Ruizeng Yang, Haoen Zhang, Haoran Gao, Zhuoqun Gao, Jiayan Yan, Zhifeng Jiang, Shiyu Zhang, Xueyan Ma, Jing Yu, Fang Wei, Qiang Fu, Yi Zhou, Jian Zhou, Jian Wan, Yunyun Jin, Lei Zhang
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.