Gut microbiota-derived 3-indoleacrylic acid mediates ferulic acid protection against aflatoxin B1 hepatotoxicity via AhR-ferroptosis inhibition

Here, we discover that a cereal-derived polyphenol, ferulic acid (FA), alleviates AFB1-induced hepatotoxicity by remodeling gut microbiota and activating microbial tryptophan (Trp) metabolism. Specifically, dietary FA enriches P. anaerobius, enhancing microbial conversion of Trp to 3-indoleacrylic acid (IA) both in vivo and in vitro.

Mechanistically, by combining single-cell RNA sequencing and surface plasmon resonance, we demonstrate that IA functionally antagonizes AFB1-induced hyperactivation of the AhR pathway, thereby suppressing AhR-driven ferroptosis. This functional mechanism was validated through genetic knockdown and pharmacological interventions. Crucially, we reveal that IA ameliorates AFB1-induced liver inflammation by reprogramming the subset composition and function of macrophages, which was confirmed by macrophage-depletion models.