Integrated Multi-Omics Analysis Reveals Complex Cytotoxicity-Associated Molecular Response Patterns of Representative Toxins from Four Classes of Lipophilic Algal Toxins in Neuro-2a Cells.

Lipophilic marine toxins (LMTs) are important toxic risk factors in marine ecosystems and seafood safety, yet the comparative cytotoxicity-associated molecular responses of different LMT classes remain unclear. Here, Neuro-2a cells were exposed to four representative LMTs-dinophysistoxin-1 (DTX1), azaspiracid-3 (AZA3), yessotoxin (YTX), and pectenotoxin-2 (PTX2)-and acute cytotoxicity was evaluated together with integrated transcriptomic, proteomic, and metabolomic analyses. Cell viability assays showed a cytotoxic potency order of DTX1 > AZA3 > YTX > PTX2. Integrated multi-omics analysis revealed that DTX1, the most cytotoxic toxin, caused the broadest molecular perturbations, mainly involving mitochondrial energy metabolism, p53-mediated stress responses, and multilayered metabolic networks. AZA3 and YTX induced intermediate cytotoxicity and showed partially similar perturbation patterns, particularly affecting cytoskeleton-related, immune-related, and metabolism-related processes. In contrast, PTX2, the least cytotoxic toxin, produced more limited responses mainly involving tyrosine metabolism and the cGMP-PKG signaling network. Overall, molecular perturbation patterns generally corresponded to acute cytotoxic potencies, while each toxin exhibited distinct key pathways and functional modules. These findings provide a multi-omics basis for cytotoxic responses of representative LMT classes and guide subsequent functional validation.