Arsenic-induced hepatotoxicity: Mechanistic insights into TNFAIP3-mediated regulation of the NF-κB p65/IAPs Signaling Pathway

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Exposure to excessive arsenic results in progressive liver injury, although the underlying mechanisms are not yet fully elucidated. This study aims to investigate whether TNFAIP3 plays a protective role within the transcriptional regulatory network linking with NF-κB p65 and IAPs. A model of arsenic-induced liver injury in C57BL/6 mice was established, alongside an in vitro study using HHL-5 cells. The Cell Counting Kit-8 was employed to measure cell viability. Western blotting and qRT-PCR were used to analyze protein and mRNA levels, respectively. Flow cytometry was used to assess the apoptosis rate of the cells. Cell transfection techniques were applied to investigate the interactions among relevant molecules. The in vivo study revealed pathological abnormalities in mice exposed to water arsenic, alongside significant up-regulation of cleaved caspase-3 (P < 0.05). In vitro, treatment of sodium arsenite resulted in reduced cell viability, increased levels of cleaved caspase-3, and elevated apoptosis rates in HHL-5 cells (all P < 0.05). Inhibition of NF-κB further reduced the expression of NF-κB p65 and IAPs (cIAP1, cIAP2, XIAP, and Survivin) (all P < 0.05). Silencing TNFAIP3 exacerbated apoptosis and downregulated NF-κB p65 and IAPs (all P < 0.05), highlighting their protective role in arsenic-induced hepatotoxicity. This study reveals that TNFAIP3 acts as a transcriptional hub gene linking NF-κB p65, influencing the expression of downstream anti-apoptotic proteins such as cIAP1, cIAP2, XIAP, and Survivin. These findings indicate that TNFAIP3 may serve as a potential therapeutic target for arsenic-induced liver injury, offering novel insights into the targeted mechanistic study.