Abstract Acquired resistance to sorafenib remains a major obstacle in the treatment of advanced hepatocellular carcinoma (HCC). While inducing ferroptosis represents a promising strategy to overcome this resistance, the specific molecular drivers underlying ferroptosis evasion in this context remain poorly defined. Here, we identified Aurora Kinase A (AURKA) as a central, actionable regulator of ferroptosis resistance in sorafenib-resistant HCC. AURKA was significantly upregulated in resistant cells and clinical specimens, which correlated with a suppressed ferroptotic state. Mechanistically, we discovered that AURKA directly interacted with and phosphorylated the ferritinophagy receptor NCOA4 at specific serine residues (S186/S234/S492), thereby competitively disrupting the NCOA4-FTH1 complex. This disruption inhibited ferritinophagic degradation of FTH1, stabilized the iron-storage protein, and limited the intracellular labile iron pool required for ferroptosis execution. Genetic or pharmacological inhibition of AURKA restored NCOA4-mediated ferritinophagy, synergized with ferroptosis inducers (sorafenib or IKE), and potently suppressed tumor growth both in vitro and in vivo. Clinically, high co-expression of AURKA and FTH1 predicted an unfavorable prognosis of HCC patients. Our study delineated the first direct link between AURKA kinase activity and the ferritinophagy machinery, establishing the AURKA-NCOA4-FTH1 axis as a master regulator of ferroptosis resistance in sorafenib-resistant HCC. These findings provide both a novel prognostic biomarker and a mechanistically grounded therapeutic strategy to overcome acquired resistance.
Zhu et al. (Fri,) studied this question.