Organic selenium: concentration-dependent redox regulation in health and disease.

Abstract

Selenium is an essential trace element for human health and exhibits a typical U-shaped dose-response relationship. Organic selenium exhibits potential in pre-clinical investigations for the treatment of various diseases, including cancer. However, its dual protective and cytotoxic effects, together with the controversial "selenium paradox": at physiological concentrations, selenium exerts antioxidant and immunomodulatory effects; at higher concentrations, it can exhibit toxicity and promote oxidative processes have hindered its clinical translation. China's heterogeneous soil selenium distribution results in marked regional differences in population selenium status. By contrast, age, body mass index, smoking, and alcohol consumption have limited effects on selenium status. These findings provide important regional evidence supporting population-stratified selenium interventions and help explain the heterogeneous manifestations of the selenium paradox across different populations. This review summarizes findings from the past two decades, focusing on the regulation of redox homeostasis, the context-dependent functions of selenoproteins, and tumour microenvironment heterogeneity. We highlight how organic selenium compounds, through metabolic processing supplying selenium for selenoprotein biosynthesis and generating methylselenol, regulate oxidative stress, the cell cycle, apoptosis, tumour-cell local invasion, and antitumour immunity. These effects are mediated by a network of selenoproteins, including but not limited to glutathione peroxidases (GPx), thioredoxin reductases (TrxR), and selenoprotein P (SELENOP), as well as by the redox-modulatory properties of methylselenol. Current controversies primarily arise from differences in selenium dose, chemical speciation, baseline selenium status, genetic background, and tumour heterogeneity. Personalized interventions based on selenium form, individual physiological characteristics, and genetic background are essential for resolving the selenium paradox and advancing clinical translation. Unlike previous reviews that have focused primarily on therapeutic efficacy, this review proposes a mechanistic framework for the concentration-dependent redox regulation of organic selenium.

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