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Patients with IBD are at increased risk for colitis-associated colorectal cancer (CACRC) compared to the general population. CACRC is preceded by IBD, characterized by highly heterogenous, pharmacologically incurable, pertinacious, worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the duration and severity of inflammation, which is influenced by the exogenous free hemoglobin alpha chain (Hb\u03b1C), a byproduct of infiltrating immune cells; extravasated erythrocytes; and macrophage erythrophagocytosis. The exogenous free Hb\u03b1C prompts oxygen free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS), which is exacerbated by decreased tissue antioxidant defenses. Mitigation of the Fenton Reaction via pharmaceutical therapy would attenuate ROS, promote apoptosis and DNAD repair, and subsequently prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C\/E). Haptoglobin\u2019s clearance rate from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial. Further, deferoxamine\u2019s hydrophilic structure limits its ability to cross cell membranes. Finally, the effectiveness of flavonoids, natural herb antioxidants, is associated with the high reactivity of hydroxyl substituents. Multiple analyses are currently underway to assess the clinical context of CACRC and outline the molecular basis of Hb\u03b1C-induced ROS pathogenesis by exposing colonocytes and\/or colonoids to Hb\u03b1C. The molecular immunopathogenesis pathways of CACRC herein reviewed are broadly still not well understood. Therefore, this timely review outlines the molecular and immunological basis of disease pathogenesis and pharmaceutical intervention as a protective measure for CACRC.<\/jats:p>","DOI":"10.3390\/medicina59071254","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T01:41:36Z","timestamp":1688694096000},"page":"1254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Inflammatory Bowel Disease-Associated Colorectal Cancer: Translational and Transformational Risks Posed by Exogenous Free Hemoglobin Alpha Chain, a By-Product of Extravasated Erythrocyte Macrophage Erythrophagocytosis"],"prefix":"10.3390","volume":"59","author":[{"given":"Maya A.","family":"Bragg","sequence":"first","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Williams A.","family":"Breaux","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1728-8456","authenticated-orcid":false,"given":"Amosy E.","family":"M\u2019Koma","sequence":"additional","affiliation":[{"name":"School of Medicine, Division of Biomedical Sciences, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1097\/MIB.0000000000000144","article-title":"Implications of the Colonic Deposition of Free Hemoglobin-alpha Chain: A Previously Unknown Tissue By-product in Inflammatory Bowel Disease","volume":"20","author":"Myers","year":"2014","journal-title":"Inflamm. 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