Role of selenoprotein S downregulation in T-2 toxin-induced endoplasmic reticulum stress and myocardial injury.

T-2 toxin, a potent Class A trichothecene mycotoxin, is a global food contaminant with poorly understood cardiotoxic mechanisms. Epidemiological evidence links T-2 toxin exposure to cardiac injury and selenium deficiency, yet the molecular basis of this interaction remains unclear. Selenoprotein S (SelS), an endoplasmic reticulum (ER)-resident selenoprotein, is critically involved in ER stress regulation and its expression correlates positively with selenium intake. This study investigates the role of SelS in T-2 toxin-induced myocardial damage and its mechanistic link to ER stress. Using in vitro models (AC16 human and H9C2 rat cardiomyocytes), it was demonstrated that T-2 toxin concentration-dependently upregulates ER stress markers (GRP78 and CHOP) while significantly downregulating SelS, correlating with reduced cell viability. A SelS gene knockout mouse model further reveals that SelS deficiency or T-2 toxin exposure independently induces cardiomyocyte death, myocardial fibrosis, and elevated cardiac enzyme (LDH, AST, CK, CK-MB) activity. The experimental groups included the control group, T-2 toxin exposure group, SelS-/- group, and SelS-/- + T-2 toxin group. Notably, combined exposure shows no additive effects, suggesting overlapping pathways: both conditions trigger similar ER stress and inflammatory responses (e.g., TNF-α and IL-6 upregulation). Mechanistically, T-2 toxin and SelS deficiency converge on ER stress-mediated myocardial inflammation, with T-2 toxin-mediated cardiotoxicity functionally converging onto SelS-dependent pathways. Bioinformatics analysis (CTD, GeneCards) confirms T-2 toxin's enrichment in inflammatory pathways, aligning with experimental findings. This work establishes SelS as a key modulator of T-2 toxin-induced cardiac toxicity, offering novel insights into ER stress-inflammation crosstalk and highlighting SelS as a potential therapeutic target for mitigating environmental toxin-related heart disease.