Targeting AhR suppresses hepatocyte ferroptosis in MASH by regulating the Pten/Akt/β catenin axis

Aryl hydrocarbon Receptor (AhR), an essential host regulator, has been observed to be significantly upregulated in patients with Metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanism remains unclear. The specific AhR antagonist CH223191 and siRNAs were employed to investigated the role of AhR and its potential as a therapeutic target for MASH in mice and hepatocytes model. Significant upregulation of hepatic AhR was found in our MASH model and across three public datasets. CH223191 (5 mg/kg) treatment effectively ameliorated lipid deposition, serum ALT/AST level, inflammatory cytokines and hepatocyte senescence. Moreover, inhibiting AhR reduced aberrant iron overload, MDA and ROS levels, and suppressed iron transporter DMT1 and iron storage protein ferritin. Furthermore, CH223191 treatment resulted in the restoration of β-catenin and Pten while reducing the phosphorylation of Akt. Suppression of Pten or β-catenin by specific antagonists significantly abolished the hepatoprotective effects of CH223191, leading to increased DMT1 and ferritin and subsequent hepatic ferroptosis in mice. In conclusions, these findings suggested a novel regulatory role of AhR plays in ferroptosis and iron overload through the Pten/Akt/βcatenin pathway, which makes AhR a promising therapeutic target for the treatment of MASH.