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HDAC inhibitors sensitize colorectal cancer to ferroptosis via m6A modification of FSP1

GSE263463 Homo sapiens Expression profiling by high throughput sequencing 6 samples Submitted 2025/04/03 Platform GPL20795
Summary
Ferroptosis therapy has been well-established in various cancers; however, colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the use of ferroptosis therapy in CRC. Through drug screening, we found histone deacetylase inhibitor (HDACi) significantly sensitized ferroptosis. Mechanically, HDACi reduced FSP1 by promoting its mRNA degradation, a known ferroptosis defense molecular. In further research, we confirmed that HDACi specifically targeted HDAC1 and suppressed the H3K27ac modification of FTO and ALKBH5. The activation of FTO and ALKBH5 resulted in a reduction of N6-methyladenosine (m6A) modification on FSP1 mRNA, leading to its degradation and ultimately sensitizing CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically reduced CRC both in vivo and in vitro. In conclusion, our research reveals how HDACi sensitized ferroptosis and prompts the combination of HDACi/ferroptosis inducers as a promising therapeutic strategy for solid tumors.
Published in
Lactylation of HDAC1 Confers Resistance to Ferroptosis in Colorectal Cancer
Yang Z, Su W, Zhang Q et al. · Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2025 · PMID 39888307 · doi:10.1002/advs.202408845
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Also filed as BioProject PRJNA1097590 and SRA study SRP500340. Searching any of these in the dataset finder brings you back here.

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