| Summary: | Aflatoxin B<sub>1</sub> (AFB<sub>1</sub>) is amongst the mycotoxins commonly affecting human and animal health, raising global food safety and control concerns. The mechanisms underlying AFB<sub>1</sub> toxicity are poorly understood. Moreover, antidotes against AFB<sub>1</sub> are lacking. Genome-wide CRISPR/Cas9 knockout screening in porcine kidney cells identified the transcription factor BTB and CNC homolog 1 (BACH1) as a gene required for AFB<sub>1</sub> toxicity. The inhibition of BACH1 expression in porcine kidney cells and human hepatoma cells resulted in increased resistance to AFB<sub>1</sub>. BACH1 depletion attenuates AFB<sub>1</sub>-induced oxidative damage via the upregulation of antioxidant genes. Subsequently, virtual structural screening identified the small molecule 1-Piperazineethanol, α-[(1,3-benzodioxol-5-yloxy)methyl] -4-(2-methoxyphenyl) (M2) as an inhibitor of BACH1. M2 and its analogues inhibited AFB<sub>1</sub>-induced porcine and human cell death in vitro, while M2 administration significantly improved AFB<sub>1</sub>-induced symptoms of weight loss and liver injury in vivo. These findings demonstrate that BACH1 plays a central role in AFB<sub>1</sub>-induced oxidative damage by regulating antioxidant gene expression. We also present a potent candidate small-molecule inhibitor in developing novel treatments for AFB<sub>1</sub> toxicity.
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