Selenium deficiency triggers intestinal ferroptosis in mice via oxidative stress

Selenium, an essential trace element, is inextricably linked to the pathogenesis of multiple disorders when deficient; however, the precise colonic injury provoked by selenium insufficiency and its mechanistic underpinnings remain largely elusive. In the present study, a selenium-deficient mouse model was established to dissect the molecular events underlying selenium deficiency-induced colonic damage. Our results revealed that selenium-deficient (SD) mice exhibited a marked reduction in colonic selenium content, accompanied by conspicuous lymphocytic infiltration within the colonic mucosa. Biochemical assays further demonstrated diminished glutathione (GSH) levels alongside elevated total iron and malondialdehyde (MDA) contents in colonic tissues of the SD group. Western blot analysis disclosed upregulation of p53, TFR1, ACSL4, and COX2, concomitant with downregulation of SLC7A11, GPX4, and Ferritin at the protein level; these alterations were corroborated by RT-qPCR, which showed increased mRNA transcripts of Acsl4, Ptgs2, and Tfrc, whereas Fth1 and Ftl were decreased. RNA-seq profiling identified upregulated expression of Lpcat3, Alox15, Por, and Fabp2, alongside downregulation of Slc40a1, Tjp1, and Ocln in the SD group. Immunohistochemical and immunofluorescence staining consistently confirmed reduced protein abundance of SLC7A11, GPX4, ZO-1, and Occludin. Gene Set Enrichment Analysis (GSEA) further pointed to significant enrichment of linoleic acid metabolism and calcium signaling pathways in the SD group. Collectively, these findings indicate that selenium deficiency not only triggers aberrant expression of ferroptosis-related molecules in the colon but also concomitantly compromises the integrity of the intestinal mucosal barrier. Moreover, transcriptomic data suggest a transcriptional linkage between linoleic acid metabolism/calcium signaling and the observed colonic pathology, providing novel insights into the regulatory network governing selenium homeostasis in gut health.