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Identifying biomarkers involved in their pathogenesis and diagnosis is essential for personalising care and improving treatment outcomes. This systematic review aims to highlight PFCD biomarkers and provide insights for clinical practice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review, registered at PROSPERO (CRD42024575480) and conducted in accordance with PRISMA guidelines, includes English-language studies on PFCD biomarkers published through May 2025. Searches were performed in PubMed and Scopus. Study selection and risk-of-bias assessment were conducted independently by two reviewers, according to prespecified search and eligibility criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 5242 records initially identified, 3700 were screened, and 33 studies were included (24 addressing pathogenesis and 9 diagnostic biomarkers). Variants in\n                      <jats:italic>OCTN1\/2<\/jats:italic>\n                      ,\n                      <jats:italic>NOD2, IRGM, TYK2<\/jats:italic>\n                      , and\n                      <jats:italic>VDR<\/jats:italic>\n                      genes influence fistula risk and severity in Crohn\u2019s disease, particularly polymorphisms in\n                      <jats:italic>IRGM, NOD2<\/jats:italic>\n                      , and genes within the JAK\u2013STAT signalling pathway. Altered microbiota and the presence of antibiotic resistance genes support a bacterial role in pathogenesis. Key pro-inflammatory cytokines (IL-1\u03b2, TNF-\u03b1, IL-6) and cellular populations (CD4\u207a T-cells, macrophages) drive inflammation, while epithelial-mesenchymal transition and extracellular matrix remodelling contribute to fistula persistence. Recent evidence suggests that PFCD arises from complex immune-stromal cell interactions, involving cellular senescence, epigenetic alterations, and population heterogeneity. Diagnostic advances include metabolic profiling and urinary Raman spectroscopy, alongside established biomarkers such as granulomas, faecal calprotectin, and NGAL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This review highlights several promising biomarkers involved in the pathogenesis and diagnosis of PFCD; however, heterogeneity across studies limits their immediate translation into clinical guidelines. Larger, well-designed studies are needed to validate these biomarkers and support personalised treatment strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10151-026-03376-8","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T09:08:29Z","timestamp":1782119309000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Biomarkers in the pathogenesis and diagnosis of Crohn\u2019s perianal fistulas: a systematic review"],"prefix":"10.1007","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0345-0432","authenticated-orcid":false,"given":"A. 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