Se-methylselenocysteine alleviates sepsis-associated inflammation by upregulating GPX4 to inhibit macrophage...

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, with limited therapeutic options. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a key driver of septic inflammation and organ injury. GPX4 serves as the master negative regulator of ferroptosis and plays a critical role in maintaining redox homeostasis. However, strategies to directly enhance GPX4 expression remain challenging, as GPX4 is a selenoprotein whose synthesis depends on selenium bioavailability. Here, we investigated whether Se-methylselenocysteine (MSC), an organic selenium compound approved as a nutritional fortifier, alleviates sepsis by providing bioavailable selenium to support GPX4 expression and inhibit ferroptosis. In LPS-induced endotoxemic mice, MSC improved survival, reduced pro-inflammatory cytokines, and attenuated multi-organ damage. In LPS-stimulated macrophages, MSC suppressed inflammatory cytokine production and NF-κB activation. RNA-sequencing revealed that MSC reversed LPS-induced enrichment of the ferroptosis pathway. Mechanistically, MSC restored GPX4 expression, reduced lipid peroxidation, intracellular ROS, and mitochondrial damage. Pharmacological inhibition of ferroptosis with Erastin or RSL3 partially reversed the protective effects of MSC, while genetic knockdown of GPX4 largely abrogated its anti-inflammatory actions. Collectively, these findings demonstrate that MSC alleviates septic inflammation by upregulating GPX4 to inhibit macrophage ferroptosis, offering a promising therapeutic strategy for sepsis.