Figure 5.

Regulatory factors involved in sensitivity and resistance to ferroptosis in HCC patients treated with sorafenib. These regulatory factors mainly participate in sensitivity and resistance to ferroptosis in HCC cells treated with sorafenib through three pathways. (A) Labile iron pool: Inhibition of CISD2 promotes excessive iron accumulation through autophagy, resulting in sorafenib-induced ferroptosis in resistant cells. LIFR sensitizes HCC cells to sorafenib-induced ferroptosis through NF-κB inhibition and the subsequent downregulation of iron-sequestering LCN2. (B) The biosynthesis of PUFAs: Activation of the HBXIP/SCD axis via coactivation of ZNF263 reduces the anticancer activity of sorafenib and suppresses ferroptosis. MiR-23a-3p acts as a direct suppressor of ferroptosis by targeting the 3'UTR of ACSL4. The ETS1/miR‑23a‑3p/ACSL4 axis contributes to sorafenib resistance in HCC by regulating ferroptosis. Inhibition of the Hippo signalling pathway can activate YAP to promote the transcription of ACSL4, thereby promoting ferroptosis. The interaction mediated by E-cadherin in HepG2 cells suppresses ferroptosis by activating the intracellular NF2 and Hippo signalling pathways. (C) The defensive system against ferroptosis: In sorafenib-resistant HCC cells, YAP/TAZ and ATF4 are activated in the nucleus where they induce SLC7A11 expression. AKR1C3 suppresses ferroptosis through the regulation of YAP/SLC7A11. Binding between BECN1 and SLC7A11 increases, which inhibits the activity of System Xc^- and the triggering of ferroptosis in sorafenib-treated HCC cells via the SHP-1/STAT3/MCL1 axis. C8orf76 and DAZAP1 reduce cellular sensitivity to sorafenib by acting on SLC7A11 through different mechanisms. Additionally, targeting the FASN/HIF1α/SLC7A11 pathway could resensitize HCC cells to sorafenib. S1R and macropinocytosis negatively regulate sorafenib-induced ferroptosis.