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Persistent inflammation is a key driver of IBD-associated tumorigenesis, yet the transcriptional regulators linking inflammatory signaling to epithelial transformation remain incompletely defined. FOSL1 (FOS-like antigen 1), a member of the activator protein-1 (AP-1) transcription factor family, has emerged as a critical mediator at the intersection of inflammation, epithelial homeostasis, and cancer progression. FOSL1 is induced by pro-inflammatory pathways commonly activated in IBD, including MAPK\/ERK, NF-\u03baB, and cytokine signaling, and regulates gene programs involved in cell proliferation, migration, barrier integrity, immune modulation, and survival. Accumulating evidence demonstrates that FOSL1 expression is elevated in inflamed intestinal mucosa and in IBD-associated malignancies, where it contributes to epithelial dysfunction, chronic inflammation, tumor initiation, metastasis, angiogenesis, and therapeutic resistance. Moreover, FOSL1-driven transcriptional networks show mechanistic overlap between IBD-associated colorectal cancer (CRC) and other inflammation-linked gastrointestinal cancers, such as pancreatic ductal adenocarcinoma (PDAC). In this review, we summarize current knowledge on the regulation and function of FOSL1 in intestinal inflammation and IBD-associated cancers, highlight its context-dependent roles in epithelial and immune compartments, and discuss emerging therapeutic strategies aimed at indirectly targeting FOSL1 signaling pathways.<\/jats:p>","DOI":"10.3390\/biom16050647","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:34:42Z","timestamp":1777458882000},"page":"647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of FOSL1 in Inflammatory Bowel Disease (IBD) Pathogenesis and IBD-Associated Tumorigenesis"],"prefix":"10.3390","volume":"16","author":[{"given":"Grace J.","family":"Rilee","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, 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 23298-0540, USA"},{"name":"Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, 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 23298-0540, USA"},{"name":"Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, USA"}],"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 23298-0540, USA"},{"name":"Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, USA"},{"name":"Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-0540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.cgh.2018.08.001","article-title":"Functional Gastrointestinal Symptoms in Patients with Inflammatory Bowel Disease: A Clinical Challenge","volume":"17","author":"Colombel","year":"2019","journal-title":"Clin. 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