{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:23:04Z","timestamp":1785424984147,"version":"3.56.0"},"reference-count":64,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIGMS","award":["R01GM132396"],"award-info":[{"award-number":["R01GM132396"]}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["RSG-21-036-01-TBE"],"award-info":[{"award-number":["RSG-21-036-01-TBE"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RSG-21-036-01-TBE"],"award-info":[{"award-number":["RSG-21-036-01-TBE"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The maintenance of gastrointestinal homeostasis relies on a tightly coordinated interplay between the intestinal epithelium, the immune system, and the commensal microbiome. Disruption of this balance underlies inflammatory bowel disease (IBD), encompassing Crohn\u2019s disease and ulcerative colitis, and is characterized by chronic, relapsing mucosal inflammation driven by genetic susceptibility, environmental factors, immune dysregulation, and microbial imbalance. Persistent inflammation promotes repeated cycles of epithelial injury and aberrant repair, creating a permissive environment for dysplasia and the development of colitis-associated cancer, most notably colorectal carcinoma. Recent evidence identifies the anti-apoptotic regulator myeloid cell leukemia-1 (Mcl1) as a critical determinant of epithelial integrity and cellular turnover during mucosal stress. Loss or destabilization of Mcl1 disrupts epithelial homeostasis, amplifies inflammatory signaling, and accelerates tumor initiation, whereas its adaptive upregulation in established malignancy promotes tumor cell survival, metabolic fitness, and therapeutic resistance. Thus, Mcl1 functions as a context-dependent molecular switch via restraining malignant transformation during chronic inflammation while supporting tumor progression once neoplasia is established. This functional duality positions Mcl1 as both a biomarker of disease progression and a therapeutically actionable vulnerability. In this review, we synthesize recent advances elucidating how Mcl1 integrates epithelial cell-fate decisions, immune signaling and tumor evolution across the IBD\u2013cancer continuum. We further support these concepts through integrative analyses of multiple transcriptomic datasets comparing normal colonic mucosa with colorectal tumors, and we discuss emerging pharmacological strategies targeting Mcl1 in colitis-associated cancer.<\/jats:p>","DOI":"10.3390\/biom16050694","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T12:15:07Z","timestamp":1778156107000},"page":"694","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mcl1 as a Molecular Switch Linking Inflammatory Bowel Diseases to Colorectal Tumorigenesis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0353-1643","authenticated-orcid":false,"given":"Ahmed M.","family":"Elshazly","sequence":"first","affiliation":[{"name":"Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9236-5140","authenticated-orcid":false,"given":"Jiong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4874-8960","authenticated-orcid":false,"given":"Guang-Yu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5211-9498","authenticated-orcid":false,"given":"Senthil K.","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2147\/JIR.S65979","article-title":"Inflammatory bowel disease: Clinical aspects and treatments","volume":"7","author":"Fakhoury","year":"2014","journal-title":"J. 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