Luteolin alleviates sorafenib-induced ferroptosis of BRL-3A cells through modulation of the Nrf2/GPX4 signaling pathway

Background: Luteolin is a flavonoid chemical that exists in a variety of medicinal and edible plants and holds many biologically active properties in liver protection, anti-cancer, antioxidants, anti-inflammatory, neuroprotective, etc. According to its hepatoprotective properties, luteolin was selected to co-treat with sorafenib, one of the approved protein kinase inhibitors, to reduce sorafenib-induced normal liver cell damage. Methods: The BRL-3A cell line was treated with sorafenib to establish a liver injury model, followed by luteolin treatment. The cell viability was detected, and the mechanism of action was detected by immunofluorescence, western blotting, and real-time quantitative PCR. Results: The research findings demonstrated that luteolin could increase cystine/glutamate transporter xCT (SLC7A11) and glutathione peroxidase 4 (GPX4) expression and display a chelating effect on iron, which led to increased glutathione and decreased malondialdehyde, Fe2+ and lipid reactive oxygen species contents in BRL-3A cells, and the sorafenib-induced mitochondrial membrane potential decrease was also inhibited. In addition, when sorafenib caused the accumulation of lipid reactive oxygen species, luteolin could help release this oxidative stress by activating nuclear factor E2-related factor 2 (Nrf2) and up-regulating the expression of the associated genes heme oxygenase 1 (HO-1) and quinone oxidoreductase 1 (NQO1). Conclusion: Therefore, luteolin may ameliorate sorafenib-induced ferroptosis by activating the Nrf2-associated pathway without any impact on sorafenib anti-cancer activity. It can be used as an adjuvant to sorafenib to reduce liver injury in patients with hepatocellular carcinoma.