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GCS overexpression is a cause of drug resistance and enriches cancer stem cells (CSCs) during cancer chemotherapy. Previous studies showed that GCS modulates the expression of p53 mutants and oncogenic gain-of-function (GOF) in heterozygous knock-in cell models (TP53 R273H\u2212\/+). However, it is unclear whether GCS can modulate the effects of homozygous p53 mutations, which are common in many cancer cases. We report herewith that inhibition of GCS, via UGCG knockout and using an inhibitor (Genz-161), effectively re-sensitizes drug resistance and diminishes CSCs in colon cancer cells carrying the homozygous p53 R273H mutation. In aggressive WiDr cells carrying TP53 R273H mutation, knockout of UGCG gene using CRISPR\/Cas9 editing or inhibition of GCS with Genz-161 sensitized cancer cells to oxaliplatin, irinotecan and paclitaxel. With decreased ceramide glycosylation in lipidomic profiling, both UGCG knockout and Genz-161 treatments substantially decreased wound healing, and diminished CSCs and tumor growth under chemotherapy. Interestingly, inhibition of RNA m6A methylation by neplanocin A markedly increased p53 function and reversed drug resistance. Mechanistic investigation revealed that GCS inhibition downregulated methyltransferase-like 3 (METTL3) expression and decreased RNA-m6A modification on mutant p53 R273H effects. Altogether, our findings demonstrate that ceramide glycosylation promotes METTL3 expression and RNA m6A methylation in response to drug-induced stress, thereby promoting mutant p53 expression and associated GOF. Conversely, inhibition of GCS can diminish CSCs and drug resistance via reduction in m6A modification and advance of p53-assocaited tumor suppressive function. GCS inhibition is an achievable approach for mutant cancer treatment.<\/jats:p>","DOI":"10.3390\/ijms27073237","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T14:09:54Z","timestamp":1775138994000},"page":"3237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Suppression of Glucosylceramide Synthase Reverses Drug Resistance in Cancer Cells Harboring Homozygous p53 Mutants"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2359-4481","authenticated-orcid":false,"given":"Md Saqline","family":"Mostaq","sequence":"first","affiliation":[{"name":"School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8296-3542","authenticated-orcid":false,"given":"Mohammad N.","family":"Amin","sequence":"additional","affiliation":[{"name":"School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Raphael","sequence":"additional","affiliation":[{"name":"School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Asbury","sequence":"additional","affiliation":[{"name":"Division of Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Monroe, LA 71203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anish","family":"Gupta","sequence":"additional","affiliation":[{"name":"Division of Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Monroe, LA 71203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-2413","authenticated-orcid":false,"given":"Xianlin","family":"Han","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davorka","family":"Sekulic","sequence":"additional","affiliation":[{"name":"Global Medical Affairs, RD Hematology, Sanofi, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Michalak","sequence":"additional","affiliation":[{"name":"Division of Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Monroe, LA 71203, USA"},{"name":"Center for One Health Research, VA-MD College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA"},{"name":"Institute of Evolution, University of Haifa, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Monroe, LA 71203, USA"},{"name":"Center for One Health Research, VA-MD College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7968-0162","authenticated-orcid":false,"given":"Yong-Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bataller, M., Sanchez-Garcia, A., Garcia-Mayea, Y., Mir, C., Rodriguez, I., and Lleonart, M.E. 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