Selenoprotein K mediates selenium‑driven gastric protection by dual suppression of NF-κB-driven apoptosis and necroptosis

Chronic gastritis represents a major risk factor for gastric cancer, underscoring the urgent need for precise molecular targets to control inflammation. Selenium (Se) exerts anti-inflammatory effects through selenoproteins, yet the contribution of key selenoproteins to gastric health remains largely undefined, with selenoprotein K (SelK) being particularly poorly understood. The gastroprotective effects and molecular mechanisms of Se and SelK were investigated using sodium salicylate-induced chronic gastritis mouse models and gastric epithelial cells with SelK knockdown. Se significantly suppressed NF-κB phosphorylation, thereby rescuing tight junction integrity by inhibiting mitochondrial apoptosis (reduced Bax/Bcl-2 ratio) and RIP1/RIP3/MLKL-dependent necroptosis. Conversely, SelK deficiency activated the NF-κB pathway, upregulating pro-apoptotic proteins (caspase-7, caspase-9, caspase-3, and Bax/Bcl-2 ratio) and necroptotic proteins (RIP1/RIP3/MLKL pathway), thereby exacerbating tight junction disruption (ZO-1, claudin-1, N-cadherin, and E-cadherin). Collectively, these findings identify SelK as the critical mediator of Se’s gastric protective effects, acting through dual inhibition of apoptosis and necroptosis via NF-κB suppression to preserve gastric integrity. These findings establish SelK as a previously unrecognized key node in gastric protection and provide a rationale for SelK-targeted therapeutic strategies and Se-based nutritional interventions for gastritis management.