Figure 3.

NRF2 is involved in preventing lipid peroxidation and ferroptosis in HCC. Upon exposure of HCC cells to specific ferroptosis inducers, such as sorafenib, erastin and RSL3, the expression of P62 increases, which prevents degradation of the NRF2 protein by competitively binding to the Keap1 protein. This process also promotes the entry of NRF2 into the nucleus to initiate the transcription of downstream ferroptosis-related proteins, including GPX4, SLC7A11, HO-1, NQO1, GSR and FTH1. Many studies have shown that various proteins affect the sensitivity of HCC cells to ferroptosis via the NRF2 pathway. TSPO inhibits ferroptosis in HCC cells through the P62/KEAP1/NRF2 antioxidant pathway. SLC27A5 inhibits the NRF2/GSR pathway to reduce GSH in sorafenib-sensitive HCC cells. PCDH20 promotes ferroptosis by suppressing the expression of SIRT1 and thus promoting NRF2 acetylation in HCC. FNDC5 activates NRF2 through the PI3K/AKT pathway, conferring resistance to ferroptosis. AdipoR1, IGF2BP3, CPLX2 and CEP290 inhibit ferroptosis in liver cancer cells by activating the NRF2 pathway. GSTZ1 and QSOX1 enhance the sensitivity of HCC cells to sorafenib-induced ferroptosis via inhibition of the NRF2 pathway. Furthermore, APE1 inhibition promotes the degradation of NRF2 through the AKT/GSK3β-mediated ubiquitin‒proteasome pathway and subsequently suppresses the NRF2/SLC7A11/GPX4 axis, thereby facilitating ferroptosis.