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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302491 | GEO | 2026/03/11

REPOSITORIES: GEO

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	GSE302491_gene_expression.txt.gz	Txt

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Project description:Immunometabolism is a growing field that centers on a core paradigm: perturbations in metabolism alter a cell’s biological response in immunity and, likewise, inflammatory signals, such as cytokines and pathogens, can directly influence cellular metabolism. Although the carbons within cholesterol cannot be used for catabolic energy production, there is a growing appreciation that a similar relationship exists between cholesterol homeostasis and immunity. The majority of this literature is focused on cholesterol dynamics in the context of leukocyte immunobiology. However, the endothelium also plays an important role during the acute inflammatory response. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury. Dysregulation or aberrant activation of ECs leads to disease, such as atherosclerosis. I studied the role of cholesterol and its master regulator, SREBP2, in the EC response to acute inflammatory stress. ECs treated with cytokines upregulated SREBP2 cleavage and classical cholesterol biosynthesis gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-kB DNA binding and classical SCAP-SREBP2 processing. We used bacterial cytolysin probes to show that inflammatory stress significantly decreased accessible cholesterol, leading to dysfunctional sterol sensing and downstream SREBP2 cleavage. We also explored what role SREBP2 plays in the EC inflammatory response. Loss of SREBP2 in ECs treated with inflammatory cytokine altered EC phenotype, which was defined by decreased chemokine expression and increased type I inflammatory signaling. Interestingly, this effect on the EC inflammatory transcriptome could not be accounted by changes in cholesterol, but rather through SREBP2 binding to promoters of pro-inflammatory transcription factors. Preliminary results revealed that BHLHE40 and KLF6 are direct targets of SREBP2 and that loss of one of KLF6 could mimic the effect of SREBP2 knockdown on chemokine expression. This study is the first to provide an in-depth characterization of the relationship between SREBP2 and the endothelial acute inflammatory response.

Project description:Cholesterol homeostasis plays a central role in disease pathogenesis in chronic disorders such as cardiovascular and kidney diseases. The transcription factor SREBP2 is the main regulator of cholesterol metabolism and is central to the mechanism of action of lipid lowering drugs, such as statins, that are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic cardiovascular disease. Recently, SREBP2 has been implicated in both the innate and adaptive immune responses by upregulation of cholesterol flux or via direct transcriptional activation of pro-inflammatory genes in leukocytes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and are activated in response to damage and inflammation. The loss of SREBP2 in cultured human ECs results in significant alterations of the transcriptional response to inflammatory cytokines whereas SREBF2 knockdown inhibits the transcription and secretion of pro-inflammatory chemokines but amplifies type I interferon response genes. Furthermore, we show that SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake, but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing (ChIP-seq) of endogenous SREBP2 reveals the SREBP2 bound to the promoter regions of classical response genes as well as two non-classical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. Overexpression of SREBP2 upregulated both BHLHE40 and KLF6 transcripts independent of inflammatory stress and the transcription of these genes were found to be sensitive to cellular cholesterol levels. Of these two targets, we found that KLF6 was responsible for the amplification of chemokine expression highlighting a tight relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.

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

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