V8, a lysosomotropic wogonin derivative, alleviates hepatic steatosis by modulating GDF15-dependent mitochondrial...

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global epidemic, leading to an unmet medical need for pharmacological interventions. This study aims to investigate the protective effect and mechanism of a synthetic wogonin derivate V8 against hepatic steatosis. Herein, we report that V8 attenuates lipid accumulation and prevents mitochondrial dysfunction in hepatocytes. Growth differentiation factor 15 (GDF15), a well-known cytokine with powerful metabolic action, mediates the effect of V8 on lipid metabolic disorders. Mechanistically, due to its lysosomotropic property, V8 promotes nuclear translocation of transcription factor EB (TFEB) and subsequent GDF15 gene transcription through activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Further analysis demonstrates GDF15 mainly improves mitochondrial homeostasis under stressful condition. Consistently, Gdf15 ablation in mice results in aggravated hepatic lipid deposition and liver injury upon high-fat diet feeding. Moreover, V8 alleviates diet-induced hepatic steatosis in a GDF15-dependent manner, and improves toxins-induced hepatic pathological phenotypes accompanying with upregulation of GDF15. Collectively, these data demonstrate the beneficial metabolic effect of V8 and highlight its utility in treating hepatic steatosis and its associated metabolic complications.