Emerging <i>Alternaria</i> Toxins Drive LX-2 Cells Transdifferentiation into Myofibroblasts for Liver Fibrosis and CotA Detoxification

Alternariol (AOH), alternariol monomethyl ether (AME), and tenuazonic acid (TeA) are three major emerging <i>Alternaria</i> toxins in food. In this lncRNA-mRNA omics-based study, we first decrypt the blueprint: how emerging <i>Alternaria</i> toxins induce hepatic stellate cell LX-2 transdifferentiation for liver fibrosis. AOH and AME caused the fibrotic marker α-smooth muscle actin, extracellular matrix collagen expression, and cell contraction, while TeA had no significant effect. Mechanistically, AOH, AME, and AAT (their combination) activated the NF-κB pathway and induced ferroptosis and AMPK/AKT/m-TOR-related autophagy. Meanwhile, lncRNAs associated with hepatotoxicity were analyzed, and core LncRNAs associated with transdifferentiation were identified. Furthermore, we also proposed a CotA degradation strategy to eliminate the AOH hepatotoxicity. In summary, the present study identifies the potential hepatotoxicity of <i>Alternaria</i> toxins, introduces a CotA laccase-mediated detoxification approach, and lays a foundation for subsequent research and control strategies targeting hepatotoxicity.