The development of perianal fistulas leads to a significant decrease in the quality of patients’ lives. The onset of this condition is dependent on many factors, including inflammation or trauma. In the occurrence of Crohn’s disease-associated fistulas, numerous molecular factors and metabolic pathways are involved. To integrate the current knowledge on the biochemical, genetic, and epigenetic factors taking part in the development of perianal fistulas, we conducted a literature review. We gathered and analyzed 45 articles on this subject. The pathophysiology of fistulas associated with Crohn’s disease (CD) involves epithelial–mesenchymal transition (EMT) and matrix remodeling enzymes, with key regulators including transforming growth factor β (TGF-β), tumor necrosis factor α (TNFα), and interleukin-13 (IL-13). Genetic factors, such as mutations in receptor-interacting serine/threonine-protein kinase 1 (RIPK1), interleukin-10 receptor (IL-10R), and the MEFV gene, contribute to the onset and severity of perianal fistulas, suggesting potential therapeutic targets. Understanding the complex interplay of molecular pathways and genetic predispositions offers insights into personalized treatment strategies for this challenging condition. Further research is necessary to elucidate the intricate mechanisms underlying the pathogenesis of perianal fistulas and to identify new therapeutic interventions.

The development of perianal fistulas leads to significant decrease in the quality of patients’ lives. The onset of this condition is dependent on many factors, including inflammation or trauma. In the occurrence of Crohn’s Disease-associated fistulas, numerous molecular factors and metabolic pathways are involved. To integrate the current knowledge on the biochemical, genetic, and epigenetic factors taking part in the development of perianal fistulas, we conducted a literature review. We gathered and analyzed 39 articles on this subject. The pathophysiology of fistulas associated with Crohn’s disease (CD) involves epithelial-mesenchymal transition (EMT) and matrix remodeling enzymes, with key regulators including transforming growth factor β (TGF-β), tumor necrosis factor α (TNFα), and interleukin-13 (IL-13). Genetic factors, such as mutations in receptor-interacting serine/threonine-protein kinase 1 (RIPK1), interleukin-10 receptor (IL-10R), and the MEFV gene, contribute to the onset and severity of perianal fistulas, suggesting potential therapeutic targets. Understanding the complex interplay of molecular pathways and genetic predispositions offers insights into personalized treatment strategies for this challenging condition. Further research is necessary to elucidate the intricate mechanisms underlying the pathogenesis of perianal fistulas and to identify new therapeutic interventions.