AURKA-Mediated 7-Dehydrocholesterol Biosynthesis Drives Ferroptosis Evasion and Chemoresistance

Chemoresistance remains a major obstacle to effective colorectal cancer (CRC) treatment. While ferroptosis induction offers promise for chemosensitization, its clinical utility is limited by intrinsic resistance mechanisms. Here, we identify Aurora kinase A (AURKA) as a central ferroptosis suppressor that sustains chemoresistance by rewiring cholesterol metabolism through the SAPS3–AMPK–SREBP2 axis. Mechanistically, AURKA phosphorylates SAPS3 at Ser523/524, promoting its degradation and relieving AMPK suppression. Activated AMPK subsequently inhibits SREBP2 nuclear translocation and DHCR7 transcription, resulting in the accumulation of 7-dehydrocholesterol (7-DHC), a lipid antioxidant that confers ferroptosis resistance. Both genetic and pharmacologic inhibition of AURKA restore ferroptosis sensitivity and enhance chemotherapy efficacy in vitro and in patient-derived xenograft models. Clinically, elevated AURKA expression correlates with poor prognosis and reduced chemotherapy response in CRC patients. These findings define a novel AURKA-driven chemoresistance mechanism, revealing a regulatory nexus between cholesterol homeostasis and ferroptosis evasion, and position AURKA as a promising therapeutic target for chemosensitization in CRC.