Selenium Donor Inhibited Hepatitis B Virus Associated Hepatotoxicity via the Apoptosis and Ferroptosis Pathways

METHODS: The serum selenium level was determined in 45 patients with HBV-positive HCC (HBV(+)-HCC group), 45 patients with chronic hepatitis B virus infection (CHB group), and 45 healthy cases (HC group). The sodium selenite (Na(2)SeO(3))-treated HepG2.2.15 cells were used to observe the regulatory role of selenium on HBV replication. D-GalN/erastin-added HL7702 was used to determine the regulatory roles of Na(2)SeO(3) on hepatotoxicity or hepatocyte ferroptosis. The wild-type (WT) C57BL/6 mice and HBx-Tg mice were received lipopolysaccharide (LPS)/D-GalN, together with or without Na(2)SeO(3) administration for indicated period. Following euthanasia, the blood and liver tissue samples were collected, and specific markers were evaluated subsequently. RESULTS: The serum selenium level was downregulated in patients with HBV-positive HCC (HBV(+)-HCC group) (57.2 ± 22.5 μg/L vs. 91.8 ± 43.9 μg/L, P < 0.001), and its higher level could provide a better prognosis in these patients. The treatment using Na(2)SeO(3), a selenium donor, at high concentration (5 μM), suppressed the HBV replication by about 50% in HepG2.2.15 cells (P < 0.001), through promoting apoptotic cell death and inhibiting cellular inhibitor of apoptosis proteins (cIAPs). In addition, low-dose (500 nM) Na(2)SeO(3) could almost totally reversed the hepatotoxicity induced by hepatitis B virus X protein (HBx) (P < 0.001), which were the main causes of HCC in patients. Studies at the cellular levels showed that low-dose Na(2)SeO(3) inhibited the HBx-related hepatotoxicity by blocking ferroptosis, and glutathione peroxidase 4 (GPX4) mediated this regulatory role. Mice model results confirmed that the treatment with Na(2)SeO(3) could mitigated LPS/D-GalN-induced hepatic injury through ferroptosis pathways. CONCLUSION: Selenium regulated the dual cell death in different HCC stages via different signaling pathways, which could partly explain the anti-HBV and anti-HCC properties of selenium.