biostudies-literatureUnknown17(1)Zhou HThe role of RNA N⁶-methyladenoine (m⁶A) eraser AlkB homologue 5 (ALKBH5) in colorectal cancer (CRC) stem cells (CSCs) is unclear. Here, we find that ALKBH5 expression positively correlates with CSC markers in CRC patients. ALKBH5 induces self-renewal and stemness markers in colorectal CSCs and patient-derived organoids (PDOs). Colon-stem cell specific Alkbh5 knockin accelerates carcinogen-induced CRC, while tumorigenesis is attenuated in colon-stem cell specific Alkbh5 knockout mice. Integrated RNA-seq, MeRIP-seq and Ribo-seq reveal FAM84A as an ALKBH5 target. ALKBH5 demethylates m⁶A-modified FAM84A mRNA, causing mRNA decay and reduced expression. Mechanistically, we show that FAM84A represses CSCs by interacting with β-catenin and promoting β-catenin ubiquNature communications803https://www.ebi.ac.uk/biostudies/studies/S-EPMC12824147biostudies-literatureTargeting of the m<sup>6</sup>A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.PMC12824147Cheung HKang WYuan KWong CCChen HYu JSu HLiu WLiang CDing YWei QLi TWang SCheung AHKLuo WChen SZhou HWu YfalseTargeting of the m<sup>6</sup>A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.The role of RNA N⁶-methyladenoine (m⁶A) eraser AlkB homologue 5 (ALKBH5) in colorectal cancer (CRC) stem cells (CSCs) is unclear. Here, we find that ALKBH5 expression positively correlates with CSC markers in CRC patients. ALKBH5 induces self-renewal and stemness markers in colorectal CSCs and patient-derived organoids (PDOs). Colon-stem cell specific Alkbh5 knockin accelerates carcinogen-induced CRC, while tumorigenesis is attenuated in colon-stem cell specific Alkbh5 knockout mice. Integrated RNA-seq, MeRIP-seq and Ribo-seq reveal FAM84A as an ALKBH5 target. ALKBH5 demethylates m⁶A-modified FAM84A mRNA, causing mRNA decay and reduced expression. Mechanistically, we show that FAM84A represses CSCs by interacting with β-catenin and promoting β-catenin ubiqu2025-01-01T00:00:00Z2025 Dec2026-06-06T22:00:16.482Z2026-06-05T03:11:56.825ZS-EPMC128241474139084910.1038/s41467-025-67502-0