Selenium under the microscope: from a “narrow window of safety” to new therapeutic ideas

Selenium is a trace element with a complicated biography: since its discovery in 1817, it was considered toxic until it was discovered in 1957 that it protects vitamin E-deficient rats from liver necrosis and is essential for humans. Today, we know about 25 selenoprotein genes and dozens of processes in which they are involved - from antioxidant protection and transcription regulation to immune and reproductive functions. But selenium also has a “dark side”: a narrow safe range of consumption and different forms with very different bioavailability. All this formed the basis of a special issue of Nutrients, for which the editors collected fresh data - from cellular and animal models to studies in humans.

Background

Selenium is a paradoxical micronutrient: key enzymes of antioxidant protection and thyroid metabolism (selenoproteins of the GPx, TrxR, deiodinase family), immune and reproductive functions cannot function without it, but its “useful dose” is narrow, and the biological effect sharply depends on the form (selenite, selenomethionine/yeast, new nanoforms) and background diet. On the world map, the status of selenium is distributed in spots: in regions with poor soils, deficiency syndromes (cardiomyopathy, arthropathies) have historically occurred, while in “rich” ones there is a risk of chronic excess (selenosis), hair loss, dermatopathies. For the clinic and public health, this creates a “U-shaped” problem: both deficiency and excess are equally dangerous.

The picture is complicated by methodology and evidence.

• Status measurements: total serum Se, selenoprotein P, GPx activity - markers of different “depth”, not always interchangeable.
• Heterogeneity of interventions: organic and inorganic forms, doses “by eye”, different food matrices → different bioavailability and distribution in tissues.
• Endpoints: from molecular (redox signals, ferroptosis) to clinical (cardiovascular, liver, oncological outcomes); randomized trials with hard endpoints are not always available.
• Nutrient combinations: selenium has long been studied “in combination” (for example, with vitamin E, coenzyme Q₁₀), but the rules of “who with whom and when” are still being formed.
• Personal factors: genetics of Se metabolism, microbiota, protein-amino acid background of the diet, age and concomitant diseases change the response to the same doses.

Against this backdrop, the Nutrients themed issue was born: it systematizes where selenium actually provides benefits (and in what form), where the risks outweigh, how to combine Se with other micro- and macronutrients, and what models/biomarkers should be used in future studies. The goal is to move from the universal advice “take selenium” to precision nutrition: assessment of baseline status, balanced choice of form and dose, clear indications and safety monitoring.

What is important about selenium

• Biology: Key effects are mediated through selenoproteins (eg, the glutathione peroxidase family), which support redox homeostasis, apoptosis, CNS development, and stress resistance.
• The dose decides everything: a deficiency is fraught with immune disorders and specific diseases, an excess - with dermatitis, hair loss and a possible increase in the risk of a number of metabolic/neurological problems. The "golden mean" depends on the form (organic/inorganic Se) and the amino acid background in the diet.
• Form matters: selenite, selenomethionine/yeast, nanoparticles - these are different pharmacokinetics and tissue effects; "one selenium" ≠ "all the same".

The issue turned out to be "mosaic": the authors are not looking for one magic pill, but show where exactly microelements (including selenium) are able to change the trajectory of the disease - and where it is too early to make loud conclusions. Below are the main strokes.

What the special issue showed: key findings and trends

• Who gets their selenium and where (US, NHANES): Cross-sectional data indicate that total dietary Se is the main predictor of blood Se levels (controlling for sex, race, education, income, BMI, smoking/alcohol). A separate analysis associates selenium and manganese with better red blood cell parameters, and chromium with worse ones (blood-level associations).
• Muscles and Se Forms (Adolescent Model): Selenite and selenium nanoparticles act differently: Se-NPs worsened muscle mass and protein gain and disrupted insulin signaling, while selenite, on the contrary, "quenched" catabolism. Conclusion - therapeutic potential depends on the form.
• Liver and selenium “allies”: co-administration of coenzyme Q and Se in the MASH model reduced oxidative stress, lipid peroxidation and ferroptosis, while reducing inflammation and fibrosis. A hint for combined strategies of liver nutritional support.
• Oncology and Selol: A mixture of selenite triglycerides increased the activity of antioxidant enzymes in healthy mice and changed the morphology of tumor cells in a prostate cancer model - there is mechanistic interest, but it is far from clinical use.
• Not just Se: magnesium in Crohn's disease: meta-analysis showed lower Mg levels and intake in patients; magnesium supplements were associated with better chances of remission and improved sleep.
• Vitamin D in preschool children: a Romanian cross-sectional study supported the idea of preventing respiratory infections with sufficient vitamin D status - an argument for seasonal recommendations.
• “Food as medicine” for the kidneys: a review of botanical micronutrients (the concept of medicine-food homology) systematized the mechanisms of nephroprotection: from antioxidant pathways to inflammation modulation.

What does this mean for practice?

• Selenium - yes, but targeted:
  • assess status (diet, geography, priority groups),
  • choose a form (organic forms and yeast are often preferable to selenite in prevention; it is not transferred mechanically to therapy!),
  • avoid self-dosing: “a little bit not enough” and “a little bit too much” are separated by a narrow band.
• Think about combinations: where oxidative stress plays a role (liver in MASH, sarcopenia), combo approaches are reasonable (for example, CoQ + Se) - for now this is a hypothesis based on preclinical data.
• Look beyond selenium: Mg or vitamin D deficiencies are also clinically significant; vulnerable cohorts (IBD, children) benefit from status screening and correct supplementation.

Where are the "red lines" now?

• Selenium forms ≠ interchangeable tablets. Nanoforms and selenite produce different signals in tissue; results from animal models cannot be directly transferred to humans.
• Association does not equal causation. Most "human" data are cross-sectional: useful for hypotheses, not prescriptions. Randomized trials with inclusion biomarkers and "hard" outcomes are needed.
• Narrow "safety window". Regular "multivitamins with Se" "just in case" is a bad idea: the risk of "jumping" into excess is real, especially when consuming Se-rich foods in parallel.

Where should science move: targeted tasks for the coming years

• Deciphering the "dark horses" among selenoproteins: functions of little-studied proteins and their tissue-specific roles (brain, immunity, reproduction).
• Compare forms in the clinic: head-to-head RCTs of organic forms, selenite and (caution) nanoforms - with pharmacokinetics and tissue markers of action.
• Combination nutritional regimens: Se + CoQ in MASH, Se + protein/amino acids in sarcopenia trials - with well-designed endpoints.
• Dose personalization: taking into account the genetics of Se metabolism, background amino acid diet and microbiota to customize doses and forms.

Conclusion

The special issue does not make sensations - it brings order to where selenium (and other micronutrients) is really appropriate, and where it is important not to harm. In practice, this means "less universal schemes, more stratification": assessing the status, choosing a form, working with deficiencies and carefully adding combinations where they make biological sense.

Source: Shuang-Qing Zhang. Effects of Selenium and Other Micronutrient Intake on Human Health. Editorial to the Special Issue, Nutrients, July 7, 2025; 17(13):2239. https://doi.org/10.3390/nu17132239