Metabolic Functions and Mechanisms of Selenium, Selenocysteine, and GPX4 Mediated Immune Regulation Through Autophagy...

Selenium, an essential trace element in the human body, is present in the form of selenocysteine (Sec) within 25 selenoproteins, including selenoprotein N, selenoprotein P, and glutathione peroxidases (GPXs). An increasing number of studies have shown that selenoproteins resulting from selenium metabolism exert a significant effect on diverse immune cells. For instance, both selenoprotein K and GPX4 are intricately involved in the initiation and resolution of pro-inflammatory responses in granulocytes (PMN). The function of dendritic cells (DCs) exhibits a specific association with the expression of selenoproteins. Methionine sulfoxide reductase B1 (MSRB1) can facilitate lipopolysaccharide (LPS) in stimulating bone marrow-derived macrophages (BMDM), induce the production of anti-inflammatory cytokines interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1RA), and thereby partake in immune activities. The roles of selenoproteins in immune cells underscore their significance and complexity in the overall physiological process. In particular, their involvement in tumor immunity warrants in-depth exploration. In solid tumors, the process by which cancer cells generate selenoproteins, especially GPX4, through selenium metabolism constructs a defense mechanism against ferroptosis. This process is highly reliant on the capacity of cancer cells to take up selenium independently, as well as the activation of selenium metabolic pathways such as the trans-selenation pathway and the breakdown of inorganic selenium compounds. In the autophagy mediated by copper and erastin (a ferroptosis inducer), the autophagy receptors TAX1BP1 and SQSTM1 can promote the degradation of GPX4, effectively reducing the resistance of cancer cells to ferroptosis. This distinctive mechanism has opened up a novel perspective for research and offered potential therapeutic targets in the field of cancer treatment. In this review, we conduct a comprehensive and in-depth analysis of the roles played by selenoproteins derived from selenium metabolism in the regulation of immune cells associated with immune diseases. Moreover, we elaborate in detail on the effects of GPX4 in relation to ferroptosis in solid tumors under the influence of autophagy-mediated immunomodulation.