Aflatoxin B1 (AFB1) Accelerates the Pathological Process of Hepatic Aging by Hijacking the Aryl Hydrocarbon Receptor (AHR) Signaling Pathway
Jian Sun, Zehui Li, Yu Zhao, Bi Mao, Zhengwang Yi, Yang Zhao, Ziheng Zou, Zhijie Liu, Juyu Wang, Weijie Qu, Bundit Tengjaroensakul, Limei Zhang, Yi Wu, Xiaolong GuAbstract
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.