T-2 toxin toxicity: what do we currently know about the most toxic trichothecene mycotoxin?

T-2 toxin, a type A trichothecene mycotoxin produced by Fusarium species, is recognized as one of the most potent contaminants of cereals and cereal-based products worldwide. Despite decades of investigation, its toxicological profile continues to expand as new mechanistic insights emerge from molecular biology, omics technologies, and computational toxicology. This state-of-the-art review critically reassesses current knowledge regarding the physicochemical characteristics, environmental occurrence, exposure pathways, metabolism, and regulatory aspects of T-2 toxin, with particular emphasis on its mechanisms of action. T-2 induces pronounced e.g. oxidative stress, disrupts mitochondrial membrane potential, promotes cytochrome c release, and activates caspase-dependent apoptosis. Emerging evidence further implicates immunotoxic, neurotoxic, cardiotoxic, and nephrotoxic effects, as well as modulation of Nrf2, JAK/STAT, inflammasome, and autophagy-related pathways. The review integrates findings from in chemico, in vitro, in vivo, and New Approach Methodologies (NAMs), including QSAR and in silico modeling approaches that support predictive toxicology and risk assessment. Special attention is given to metabolic transformation into other derivatives, scenarios with other Fusarium mycotoxins, and climate-driven changes in contamination patterns. Collectively, this multidimensional synthesis highlights persistent knowledge gaps and underscores the need for integrative, mechanism-based frameworks in future regulatory evaluation of T-2 toxin with in silico methods.