Aflatoxin B1 (AFB1) Accelerates the Pathological Process of Hepatic Aging by Hijacking the Aryl Hydrocarbon Receptor (AHR) Signaling Pathway

Aflatoxin B1 (AFB1) is a environmental hepatotoxicant, yet the molecular circuitry through which it drives hepatic senescence remains incompletely defined. Employing murine models and AML-12, and demonstrated that AFB1 exposure upregulated aryl hydrocarbon receptor (AHR) expression, promoted its nuclear translocation, and elicited DNA double-strand breaks as evidenced by γ-H2AX foci formation. This genotoxic insult activated the p53/p21 checkpoint axis, downregulated CDK4/Cyclin D1, and induced G1-phase cell cycle arrest, while concurrently augmenting the senescence-associated secretory phenotype (SASP) via interleukin (IL)-6 and IL-1β upregulation. Pharmacological inhibition of AHR with CH223191 effectively abrogated these AFB1-induced molecular and pathological alterations, reversing hepatocyte injury and senescence markers. Collectively, this study defines a novel ″AFB1-AHR-aging″ axis, revealing that environmental AFB1 subverts AHR signaling to orchestrate a pro-senescent program in the liver, highlighting AHR as a potential therapeutic target for AFB1-associated hepatopathies.