Integrating Inflammatory and Epigenetic Signatures in IBD-Associated Colorectal Carcinogenesis: Models, Mechanisms, and Clinical Implications

The rising global prevalence of inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, is paralleled by an increased risk of colitis-associated colorectal cancer (CAC). Persistent intestinal inflammation promotes genetic instability and epigenetic reprogramming within epithelial and immune cells, driving the multistep transition from inflammation to neoplasia. This review integrates findings from preclinical animal models and RNA-seq data to dissect the molecular events underpinning CAC, a subset of colorectal cancer (CRC) driven by chronic inflammation. We highlight how pro-inflammatory cytokines (e.g., TNF-α, IL-6), oxidative stress, and microbial dysbiosis converge on key transcriptional regulators such as NF-κB and STAT3, inducing DNA methylation and histone modifications (e.g., H3K27me3), altering chromatin dynamics, gene expression, and non-coding RNA networks (e.g., miR-21, MALAT1, CRNDE), ultimately reshaping pathways involved in proliferation, apoptosis, and immune evasion. This review updates new potential associations of entities with these diseases, in their networks of interaction, summarizing major aspects of genetic and chromatin-level regulatory mechanisms in IBD and CRC, and emphasizing how these interactions drive the inflammatory-to-neoplastic transition. By underscoring the reversibility of epigenetic changes, we explore their translational potential in early detection, surveillance, and precision epigenetic therapy. Understanding the interplay between genetic mutations and chromatin remodeling provides a roadmap for improving diagnostics and personalized treatments in IBD-associated colorectal carcinogenesis.