NF-κB Signaling Pathway Activation in Aflatoxin B1-Induced Hepatocellular Toxicity: Molecular Crosstalk With...

The highly hepatotoxic and carcinogenic Aspergillus-derived mycotoxin aflatoxin B1 (AFB1) stimulates hepatotoxicity and hepatocarcinogenesis by activating the nuclear factor-κB (NF-κB) signaling pathway. This review summarizes the existing information on the molecular pathways of AFB1-induced hepatocellular damage and carcinogenesis through NF-κB-mediated pathways, with an emphasis on the stepwise cascade from AFB1 bioactivation to chronic inflammation. When AFB1 is taken up by the hepatocellular membrane, it is metabolically bioactivated by cytochrome P450 (CYP450) enzymes to yield reactive intermediates (including AFB1-8,9-epoxide) capable of directly covalently altering cellular macromolecules and producing reactive oxygen species (ROS). The accumulation of AFB1-derived adducts and ROS leads to the activation of the inhibitor of κB (IκB) via IKK. This activation subsequently facilitates the phosphorylation and proteasomal degradation of IκB, allowing NF-κB to translocate into the nucleus. Long-term activation of NF-κB enhances the expression of pro-inflammatory cytokines (IL-1β, TNF-α), anti-apoptotic factors, and proliferative stimuli, creating a chronic inflammatory microenvironment that permits hepatocarcinogenesis initiation. In addition, redox-sensitive signaling cascades propagate NF-κB activation through AFB1-induced oxidative stress. This review identifies some of the main contemporary issues, such as the definition of the upstream molecular sensors that mediate IKK-IKB signaling under various conditions of exposure, mapping of downstream NF-κB effector programs, and the metabolic fate of AFB1 during prolonged pathway activation, which are still of primary concern in terms of translation. In addition, we thoroughly assessed emerging pharmacological interventions targeting the AFB1-NF-κB axis, including natural polyphenols (curcumin and resveratrol), probiotics (Lactobacillus species), antioxidants (alpha-lipoic acid), and novel candidates (phillygenin and copper-albumin complexes). These interventions exert protective effects by inhibiting NF-κB, reducing oxidative stress, and controlling apoptosis. This review offers a mechanistic basis for explaining liver toxicity caused by AFB1 and prioritizes actionable therapeutic targets and future research directions to develop novel prevention and treatment options against aflatoxin-induced hepatic pathologies.