Tamarixetin promotes ferroptosis-associated redox stress and compensatory activation of nuclear factor erythroid 2-related factor 2 in hepatoma cells

Ferroptosis-associated redox vulnerability represents a potential therapeutic target in hepatocellular carcinoma, yet the interplay between this process and antioxidant adaptation remains unclear. Here, we show that Tamarixetin preferentially reduces viability in HepG2 and Huh-7 cells relative to the HepaRG comparison model. In HepG2 cells, viability loss and lipid peroxidation were partially attenuated by ferrostatin-1, while deferoxamine also partially restored viability under a higher-concentration Tamarixetin challenge. Transcriptome profiling revealed enrichment of ferroptosis- and glutathione metabolism-related pathways, implicating redox-associated genes linked to the SLC7A11–GPX4 defense axis. In parallel, Tamarixetin enhanced NRF2 downstream responses, consistent with the activation of a compensatory antioxidant program in response to redox stress. Tamarixetin reduced cystine-analog uptake and increased the oxidized-to-reduced glutathione (GSSG/GSH) ratio in HepG2 cells. Molecular docking supported a structural hypothesis for xCT interaction without establishing direct binding. Notably, Tamarixetin-induced lipid peroxidation was retained in three-dimensional hepatoma spheroids. These findings identify Tamarixetin as a context-dependent redox-active compound that promotes ferroptosis-associated injury alongside NRF2-associated antioxidant responses in hepatoma cells.