Emerging Alternaria 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 Alternaria toxins in food. In this lncRNA-mRNA omics-based study, we first decrypt the blueprint: how emerging Alternaria 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 Alternaria toxins, introduces a CotA laccase-mediated detoxification approach, and lays a foundation for subsequent research and control strategies targeting hepatotoxicity.