The present study aimed to reveal the molecular mechanism of T-2 induced cerebral edema by aquaporin-4 blocking and permeation. Aquaporin-4 (AQP4) is a class of aquaporin channels that mainly expressed in the brain, and their structural changes lead to life-threatening complications such as cardio-respiratory arrest, nephritis, and irreversible brain damage. We employed molecular dynamic simulation, text mining, in vitro and in vivo analysis to study the structural and functional changes induced by T-2 toxin on aquaporin-4. The action of toxin leads to the disrupted permeation of water and permeation coefficients are found to be affected from native (2.49 ± 0.02 x 10-14 cm³/s) to toxin treated AQP4 (7.68 ± 0.15 x 10-14 cm³/s) channel. Further, T-2 toxin forms strong electrostatic interactions at the binding site and pushes the key residues (Ala210, Phe77, Arg216, and His201) outwards at the selectivity filter. Also, the role of a histidine residue in aquaporin-4 channel was identified by alchemical transformation and umbrella sampling methods. Alchemical free energy perturbation energy for H201A↔A201H found to be 3.07 ± 0.18 kJ/mol, indicates the structural importance of the histidine residue at 201. In addition, histopathology and expression of aquaporin-4 in the Mus musculus brain tissues shows the damaged and altered expression of the protein. The text mining reveals the co-occurrence of genes/proteins associated with the AQP4 expression and T-2 toxin-induced cell apoptosis, which leads to the cerebral edema.