Deciphering sorafenib resistance in hepatocellular carcinoma via ferroptotic mechanisms

Sorafenib is a cornerstone in the treatment of advanced HCC. However, its clinical efficacy is frequently limited by the development of resistance, contributing to unfavorable patient outcomes. Overcoming this resistance is therefore a critical therapeutic challenge. Emerging evidence highlights ferroptosis-a regulated cell death process driven by iron-dependent lipid peroxidation-as a promising avenue to reverse sorafenib resistance. SLC7A11 (cystine/glutamate antiporter) and GPX4 (phospholipid hydroperoxidase) cooperate to maintain redox homeostasis by supporting glutathione biosynthesis and neutralizing lipid peroxides, thereby inhibiting ferroptosis. Nrf2, a master transcriptional regulator of antioxidant responses, further enhances this defense by upregulating both SLC7A11 and GPX4, protecting HCC cells from sorafenib-induced ferroptotic death. In contrast, lipid metabolism remodels membrane phospholipid composition to promote ferroptosis resistance. This review systematically examines the key regulatory axes modulating ferroptosis in this context: the Nrf2/SLC7A11/GPX4 antioxidant axis, the parallel FSP1-CoQ10 pathway, the pro-ferroptotic ACSL4/LPCAT3 axis, and central transcriptional regulators of SLC7A11, including P53, ATF4, SAT1, and ABCC5. We synthesize recent advances linking these molecular axes to ferroptosis pathways, discuss their crosstalk in sorafenib-resistant HCC, and underscore emerging therapeutic strategies that leverage pharmacological or radiotherapeutic targeting of these mechanisms. A deeper understanding of this regulatory network may inform rational combination therapies aimed at resensitizing advanced HCC to sorafenib.