NRF2-dependent suppression of selenoprotein P expression promotes intracellular selenium metabolic remodeling and upregulation of antioxidant selenoproteins in hepatocellular carcinoma

Selenium-containing antioxidant enzymes such as glutathione peroxidase 4 (GPx4) and thioredoxin reductase 1 (TrxR1, encoded by TXNRD1 ) have emerged as therapeutic targets in hepatocellular carcinoma (HCC), a highly treatment-resistant cancer. Hepatocytes play a central role in selenium metabolism by synthesizing and secreting selenoprotein P (SeP, encoded by SELENOP ), the major selenium containing protein in plasma, which supplies selenium to peripheral tissues. Although decreased circulating SeP levels have been associated with HCC progression and poor prognosis, the underlying mechanisms remain unclear. In this study, we reanalyzed publicly available single-cell RNA sequence data of HCC tumors and identified a distinct tumor cell cluster characterized by reduced SELENOP expression, enhanced GPX4 and TXNRD1 expression, and activation of NRF2 signaling. In HepG2 cells, pharmacological and genetic activation of NRF2 suppressed SeP expression, elevated TrxR1 levels, and promoted intracellular selenium accumulation. Consistently, SeP knockout (KO) cells exhibited increased intracellular selenium, upregulation of GPx1 and GPx4, and resistance to ferroptosis. Similarly, under selenium-deficient dietary conditions, SeP KO mice showed elevated hepatic selenium and GPx1 expression compared to wild-type controls. These findings uncover a novel NRF2-mediated selenium metabolic remodeling mechanism in HCC, in which SeP suppression promotes intracellular selenium retention and selective upregulation of antioxidant selenoproteins. This redox adaptation contributes to ferroptosis resistance and may represent a potential therapeutic axis in liver cancer. • Single-cell RNA-seq reveals a tumor cluster with low SELENOP and high NRF2 activity in HCC. • NRF2 activation suppresses SeP expression and increases intracellular selenium levels in HepG2 cells. • SeP knockout enhances antioxidant selenoproteins and protects cells from ferroptosis in vitro. • SeP-deficient mice accumulate more liver selenium and GPx1 on low-selenium diets. • The NRF2–SeP axis remodels selenium metabolism and redox balance in liver cancer.