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Background High-mobility group box protein 1 [HMGB1] is a ubiquitous nucleoprotein with immune-regulatory properties following cellular secretion or release in sterile and in infectious inflammation. Stool and serum HMGB1 levels correlate with colitis severity and colorectal cancer [CRC] progression, yet recent reports indicate that HMGB1 mainly operates as an intracellular determinant of enterocyte fate during colitis, and investigations into the roles of HMGB1 in CRC are lacking. Methods Using mice with conditional HMGB1-knockout in enterocytes [ Hmgb1 ΔIEC] and myeloid cells [ Hmgb1 ΔLysM], respectively, we explored functions of HMGB1 in pathogenetically diverse contexts of colitis and colitis-associated CRC. Results HMGB1 is overexpressed in human inflammatory bowel disease and gastrointestinal cancers, and HMGB1 protein localises in enterocytes and stromal cells in colitis and CRC specimens from humans and rodents. As previously described, enterocyte HMGB1 deficiency aggravates severe chemical-induced intestinal injury, but not Citrobacter rodentium or T cell transfer colitis in mice. HMGB1 - deficient enterocytes and organoids do not exhibit deviant apoptotic or autophagic activity, altered proliferative or migratory capacity, abnormal intestinal permeability, or aberrant DSS-induced organoid inflammation in vitro. Instead, we observed altered in vivo reprogramming of both intestinal epithelia and infiltrating myeloid cells in Hmgb1 ΔIEC early during colitis, suggesting HMGB1-mediated paracrine injury signalling. Hmgb1 ΔIEC had higher CRC burden than wild types in the Apc +/min model, whereas inflammatory CRC was attenuated in Hmgb1 ΔLysM. Cellular and molecular phenotyping of Hmgb1 ΔIEC and Hmgb1 ΔLysM cancers indicates context-dependent transcriptional modulation of immune signalling and extracellular matrix remodelling via HMGB1. Conclusion Enterocytes and myeloid cells context-dependently regulate host responses to severe colitis and maladaptive intestinal wound healing via HMGB1. [ABSTRACT FROM AUTHOR]