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Despite a steady global rise in incidence affecting more than 10 million people worldwide, current single\u2010pathway biologic and small\u2010molecule therapies still leave 30\u201340% of patients without durable remission, with progression to stricturing, fistulizing, or transmural complications. Yet the mechanistic integration of innate and adaptive immune networks, epithelial barrier dysfunction, and microbiota\u2011driven inflammation remains fragmented. This review summarizes recent advances in understanding the pathophysiological mechanisms driving IBD, focusing on innate and adaptive immune networks. Current therapies, including cytokine or integrin\u2010targeting biologics and small\u2010molecule inhibitors like Janus Kinase (JAK) antagonists, are critically evaluated in light of their restricted pathway coverage. In response to these challenges, emerging strategies are examined targeting nonimmune pathways, including microRNA\u2011124\u2010mediated gene regulation, fecal microbiota transplantation, and mesenchymal stromal cell therapies that combine immunomodulation with tissue repair. The development of effective IBD therapies is likely to benefit from combining complementary treatment strategies, guided by molecular and cellular profiling. This review underscores a paradigm shift from monotherapies to integrated, multitarget approaches as the new frontier in IBD management.<\/jats:p>","DOI":"10.1002\/mco2.70914","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:09:49Z","timestamp":1786943389000},"source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory Bowel Disease: Mechanisms and Therapeutic Advances"],"prefix":"10.1002","volume":"7","author":[{"given":"Andrea","family":"Papait","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze della Vita e Sanit\u00e0 Pubblica Universit\u00e0 Cattolica del Sacro Cuore, Largo Francesco Vito 1  Rome Italy"},{"name":"Fondazione Policlinico Universitario A. 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