Selenium (Se) is an essential trace element known for its significant role in maintaining human health and mitigating disease progression. Selenium and its compounds exhibit high selective cytotoxicity against tumor cells. However, their anti-cervical cancer (CC) effects and underlying mechanisms have not been fully explored. This study found that sodium selenite (SS) inhibits the viability of HeLa and SiHa cells in a dose- and time-dependent manner. Intraperitoneal injection of 3 and 6 mg/kg SS for 14 days in female nude mice significantly inhibited the growth of HeLa cell xenografts without evident hepatotoxicity or nephrotoxicity. RNA sequencing results indicated that the AMP-activated protein kinase (AMPK), Forkhead box protein O (FOXO), and apoptosis signaling pathways are key regulatory pathways in SS’s anti-CC effects, and SS’s inhibition of HeLa cell proliferation may be related to autophagy and ROS-induced apoptosis. Further research has revealed that SS induces cell autophagy and apoptosis through the AMPK/mTOR/FOXO3a pathway, characterized by the upregulation of p-AMPK/AMPK, FOXO3a, LC3-II, cleaved-caspase3, and cleaved-PARP and the downregulation of p-mTOR/mTOR and p62. Additionally, SS impaired mitochondrial function, including decreased mitochondrial membrane potential, mitochondrial Ca²⁺ overload, and accumulation of mitochondrial reactive oxygen species (mtROS). Pretreatment with Mitoquinone mesylate (Mito Q) and compound C partially reversed SS-induced apoptosis, autophagy, and proliferation inhibition. Pretreatment with 3-methyladenine (3-MA) enhances SS-induced apoptosis and proliferation inhibition in HeLa cells but reverses these effects in SiHa cells. In summary, SS induces apoptosis, autophagy, and proliferation inhibition in HeLa and SiHa cells through the activation of the AMPK/mTOR/FOXO3a signaling pathway via mtROS. Autophagy activation may be a major risk factor for SS-induced apoptosis in SiHa cells but can protect HeLa cells from SS-induced apoptosis. These findings provide new evidence for understanding the molecular mechanisms underlying SS in potential new drug development for CC.

Background: Selenium (Se) is an essential trace element for maintaining human health, with significant antioxidant and immunoregulatory functions. Inadequate Se intake may be associated with Keshan disease, Kashin–Beck disease, and hypothyroidism. However, effective indicators for scientifically guiding Se supplementation in Se-deficient populations are still lacking. Objectives: This study aims to explore the dynamic distribution of Se across various nutritional biomarkers and major organs in rats through a Se supplementation experiment, as well as the pairwise correlations between them, in order to identify reliable nutritional indicators for evaluating Se levels in the body. Methods: Se levels in hair, blood, and major tissues and organs were determined by atomic fluorescence spectrometry, and glutathione peroxidase (GSH-Px) levels were measured using an ELISA. Results: Se supplementation significantly increased Se levels in rat blood, hair, and major organs, as well as GSH-Px levels in blood. Se primarily accumulated in the liver and kidneys, followed by myocardium, spleen, and muscles. Serum and plasma Se were found to be the best indicators of short-term Se intake, while erythrocyte Se levels showed a stronger correlation with Se levels in tissues and organs, making it a better marker for assessing long-term Se nutritional status compared to hair Se. Conclusions: This study demonstrates the potential of erythrocyte Se levels as an indicator for evaluating long-term Se nutritional status, providing scientific evidence for Se nutritional assessments.