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The phenotype of cancer stem\u2010like cells (CSCs) presents significant hurdles for successful cancer treatment, and the expression of several CSC markers is associated with LR integrity. However, LR implications in CSCs remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study evaluated the biological and molecular functions of LRs in colorectal cancer (CRC) by using an LR\u2010disrupting alkylphospholipid (APL) drug, miltefosine. The mechanistic role of miltefosine in CSC inhibition was examined through normal or tumour intestinal mouse organoid, human CRC cell, CRC xenograft and miltefosine treatment gene expression profile analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Miltefosine suppresses CSC populations and their self\u2010renewal activities in CRC cells, a CSC\u2010targeting effect leading to irreversible disruption of tumour\u2010initiating potential in vivo. Mechanistically, miltefosine reduced the expression of a set of genes, leading to stem cell death. Among them, miltefosine transcriptionally inhibited checkpoint kinase 1 (CHEK1), indicating that LR integrity is essential for CHEK1 expression regulation. In isolated CD44<jats:sup>high<\/jats:sup> CSCs, we found that CSCs exhibited stronger therapy resistance than non\u2010CSC counterparts by preventing cell death through CHEK1\u2010mediated cell cycle checkpoints. However, inhibition of the LR\/CHEK1 axis by miltefosine released cell cycle checkpoints, forcing CSCs to enter inappropriate mitosis with accumulated DNA damage and resulting in catastrophic cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings underscore the therapeutic potential of LR\u2010targeting APLs for CRC treatment that overcomes the therapy\u2010resistant phenotype of CSCs, highlighting the importance of the LR\/CHEK1 axis as a novel mechanism of APLs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.552","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T08:16:34Z","timestamp":1636013794000},"source":"Crossref","is-referenced-by-count":28,"title":["Lipid raft\u2010disrupting miltefosine preferentially induces the death of colorectal cancer stem\u2010like cells"],"prefix":"10.1002","volume":"11","author":[{"given":"So\u2010Yeon","family":"Park","sequence":"first","affiliation":[{"name":"School of 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