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.