NRF2 Suppresses Ferroptosis by Transcriptionally Regulating SLC7A11 to Promote Chemoresistance in Hepatocellular Carcinoma

Chemoresistance remains a major obstacle in hepatocellular carcinoma (HCC).Ferroptosis is an iron-dependent cell death closely linked to drug resistance.This study investigates whether nuclear factor erythroid 2-related factor 2 (NRF2) transcriptionally regulates solute carrier family 7 member 11 (SLC7A11) to suppress ferroptosis and promote chemoresistance in HCC.The NRF2 binding site in the SLC7A11 promoter was predicted using JASPAR.NRF2 and SLC7A11 expression were detected in HCC cell lines by qRT-PCR and western blot.NRF2 was knocked down via lentiviral shRNA, and ferroptosis was assessed by intracellular ferrous iron (Fe²⁺), glutathione (GSH), and malondialdehyde (MDA) levels.Cisplatin sensitivity was evaluated by MTT, colony formation, and flow cytometry.In vivo effects were confirmed in an orthotopic HCC mouse model using cisplatin-resistant HepG2/DDP cells.Bioinformatics analysis identified a direct NRF2 binding site in the SLC7A11 promoter.Both NRF2 and SLC7A11 were significantly overexpressed in HCC cells compared to normal hepatocytes.NRF2 knockdown downregulated SLC7A11, induced ferroptosis (increased Fe²⁺ and MDA, decreased GSH), and enhanced cisplatin sensitivity, as evidenced by reduced viability, diminished clonogenicity, and increased apoptosis.The ferroptosis inducer erastin phenocopied these effects.In the orthotopic mouse model, NRF2 knockdown A c c e p t e d M a n u s c r i p t combined with cisplatin markedly suppressed tumor growth, elevated Fe²⁺ and MDA, reduced GSH, and increased TUNEL-positive cells, confirming ferroptosis engagement in vivo.Rescue experiments confirmed that SLC7A11 overexpression reversed NRF2 knockdown-induced ferroptosis and restored cisplatin resistance.NRF2transcriptionally upregulates SLC7A11 to suppress ferroptosis, thereby driving chemoresistance in HCC.Targeting the NRF2-SLC7A11 axis represents a promising strategy to overcome drug resistance.