PDCD4-driven steatosis via the HNF4A/GK axis is attenuated by the natural compound isosinensetin.

Background

Programmed cell death factor 4 (PDCD4) has been implicated in various metabolic disorders. However, its role and underlying mechanisms in metabolic dysfunction-associated steatotic liver disease (MASLD) have not been fully elucidated.

Purpose

This study aimed to define the role of PDCD4 in hepatic steatosis and identify potential therapeutic strategies targeting its downstream metabolic pathway.

Methods

RNA sequencing was performed on liver tissues from wild-type and PDCD4-knockout mice to identify dysregulated metabolic pathways and candidate downstream genes. The PDCD4-HNF4A-GK regulatory pathway was investigated using genetic, histological, biochemical, and molecular analyses in mouse models and hepatocytes. Virtual screening and molecular docking were used to identify candidate GK-targeting compounds.

Results

Hepatocyte-specific PDCD4 deletion increased hepatic GK expression and aggravated lipid accumulation. GK knockout markedly attenuated PDCD4 deficiency-induced lipid accumulation in hepatocytes. Mechanistically, PDCD4 suppressed HNF4A translation, thereby limiting HNF4A-dependent GK transcription. Virtual screening identified isosinensetin as a candidate GK inhibitor. Isosinensetin inhibited GK activity and reduced lipid accumulation in hepatocytes and CDAHFD-fed mice.

Conclusions

These results suggest that GK may warrant further investigation for ameliorating hepatic steatosis, and provide preliminary evidence for the PDCD4-HNF4A-GK axis in the regulation of hepatic triglyceride metabolism. Further studies are required to establish the relevance of this axis to the full spectrum of MASLD pathology.