Abstract

Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, represents a new potential therapeutic target in cancer. However, emerging evidence indicates that hepatocellular carcinoma (HCC) frequently exhibits resistance to ferroptosis induction, while the underlying molecular mechanism is poorly understood. Here, we found that aldo-keto reductase family 1 member C3 (AKR1C3), a protein highly expressed in ferroptosis-resistant HCC cells, negatively regulates ferroptosis in an enzyme-independent manner. Mechanistically, AKR1C3 promotes ubiquitin-proteasomal degradation of the transferrin receptor (TFRC), which is indispensable for cellular iron uptake. AKR1C3 knockdown restores TFRC expression, increases the level of labile iron pool, and sensitizes HCC cells to ferroptosis. Furthermore, AKR1C3 acts as a scaffolding protein to promote the degradation of TFRC and reduce iron uptake by promoting nuclear export of Beta-transducin repeats-containing proteins (β-TrCP) and its binding to TFRC. Notably, AKR1C3 is upregulated in NRF2-driven sorafenib-resistant HCC, and its inhibition reversed ferroptosis and sorafenib resistance. Our work uncovers AKR1C3 suppresses ferroptosis in HCC by promoting β-TrCP-mediated TFRC degradation, positioning AKR1C3 as a promising therapeutic target to enhance ferroptosis-based anticancer strategies.