# AURKA-mediated destabilization of SAPS3 drives ferroptosis evasion via 7-dehydrocholesterol biosynthesis in colorectal cancer

## TL;DR

The study reveals how a protein called AURKA helps colorectal cancer cells avoid a type of cell death called ferroptosis, offering a new target for improving cancer treatments.

## Contribution

The paper identifies a new AURKA-SAPS3-AMPK-SREBP2 pathway linking cholesterol metabolism to ferroptosis resistance in colorectal cancer.

## Key findings

- AURKA phosphorylates and destabilizes SAPS3, leading to AMPK activation and 7-DHC accumulation.
- Blocking AURKA restores ferroptosis sensitivity and improves chemotherapy in colorectal cancer models.
- High AURKA levels correlate with poor prognosis and reduced chemotherapy response in CRC patients.

## Abstract

While ferroptosis induction offers promising avenue for cancer therapeutics, its clinical utility in colorectal cancer (CRC) is limited by pervasive intrinsic resistance mechanisms. Here, we identify Aurora kinase A (AURKA) as a central suppressor of ferroptosis by rewiring cholesterol metabolism. Mechanistically, AURKA phosphorylates and destabilizes its negative regulator SAPS3 at Ser523/524, 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 delineate a novel AURKA-SAPS3-AMPK-SREBP2 axis that bridges cholesterol homeostasis and ferroptosis evasion, positioning AURKA as a promising therapeutic target for chemosensitization in CRC.