| Summary: | Zearalenone (ZEN) is one of the mycotoxins that pose high risks for human and animal health, as well as food safety. However, the regulators involved in ZEN cellular toxicity remain largely unknown. Herein, we showed that cell viability of porcine intestinal epithelial cells (IPEC-J2) tended to decrease with increasing doses of ZEN by the cell counting kit-8 assay. Expression of the <i>ISLR2</i> (immunoglobulin superfamily containing leucine-rich repeat 2) gene in IPEC-J2 cells was significantly downregulated upon ZEN exposure. Furthermore, we found the dose–effect of ZEN on <i>ISLR2</i> expression. We then overexpressed the <i>ISLR2</i> gene and observed that overexpression of <i>ISLR2</i> obviously reduced the effects of ZEN on cell viability, apoptosis rate and oxidative stress level. In addition, <i>ISLR2</i> overexpression significantly decreased the expression of <i>TNF-α</i> and <i>IFN-α</i> induced by ZEN. Our findings revealed the effects of ZEN on the <i>ISLR2</i> gene expression and indicated the <i>ISLR2</i> gene as a novel regulator of ZEN-induced cytotoxicity, which provides potential molecular targets against ZEN toxicity.
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