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Life sciences · Journal article
Antioxidants and Redox Signaling · October 7, 2026
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Aims: Selenoprotein T (SELENOT) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase implicated in redox and calcium (Ca 2+ ) homeostasis and protein quality control. Although SELENOT is highly expressed in the brain, its role in hypothalamic pro-opiomelanocortin (POMC) neurons, which regulate energy balance, remains poorly understood. We investigated whether SELENOT is required for maintaining ER homeostasis and neuronal integrity in POMC neurons. Results: Using CRISPR-edited and siRNA-silenced POMC neuronal models together with a POMC-specific SELENOT knockout mouse, we demonstrated that SELENOT loss induces a senescent-like phenotype including cellular hypertrophy, loss of neurite outgrowth, senescence-associated β-galactosidase activity, increased P16 and P21 expression, and acquisition of senescence-associated secretory phenotype. Senescence markers were elevated not only in SELENOT-deficient POMC neurons but also throughout the surrounding arcuate nucleus in vivo, suggesting propagation of a pro-inflammatory microenvironment. Mechanistically, prolonged SELENOT deficiency produced selective activation of the ATF6α arm of the unfolded protein response, depletion of ER Ca 2+ stores, and profound alterations in N -glycan maturation. Notably, leptin-induced POMC processing and secretion were spared. Glycomics revealed a shift toward immature glycans, whereas thiol-trapping proteomics identified candidate SELENOT interactors linked to ER Ca 2+ regulation. Innovation and Conclusions: This study provides the first evidence that SELENOT deficiency is sufficient to trigger cellular senescence in POMC neurons, acting as a central regulator integrating ER proteostasis, Ca 2+ homeostasis, redox adaptation, and glycosylation. These results reveal a previously unrecognized mechanism potentially linking neuronal senescence to hypothalamic dysfunction and suggest that SELENOT-dependent pathways may represent therapeutic targets for obesity, metabolic disease, and age-related neuroendocrine disorders. Antioxid. Redox Signal. 00, 000–000.