A review on MMP-2 modulating agents from natural and synthetic sources and their role in inflammatory bowel disease.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation, epithelial barrier dysfunction, immune dysregulation, and aberrant extracellular matrix (ECM) remodeling. Matrix metalloproteinase-2 (MMP-2), a zinc-dependent gelatinase, has emerged as a critical regulator of intestinal homeostasis owing to its dual role in tissue repair and inflammatory tissue destruction. Unlike several inducible matrix metalloproteinases, MMP-2 is constitutively expressed and tightly regulated through interactions with membrane-type MMPs, tissue inhibitors of metalloproteinases (TIMPs), cytokines, redox signalling, and microbial factors. Dysregulated MMP-2 activity contributes to epithelial barrier disruption, leukocyte infiltration, chronic inflammation, fibrosis, and disease progression in IBD. This review summarizes the current understanding of MMP-2 biology, activation mechanisms, and immunopharmacological functions in intestinal inflammation, while critically evaluating therapeutic strategies aimed at its modulation. Particular emphasis is placed on natural and synthetic MMP-2 modulators, including animal-derived peptides and endogenous inhibitors, plant-derived polyphenols, flavonoids, alkaloids, terpenoids, and rationally designed small-molecule and peptidomimetic inhibitors. Emerging nanocarrier-based and targeted delivery systems are also discussed as approaches to enhance selectivity and minimize systemic toxicity. Furthermore, the review highlights the limitations of broad-spectrum MMP inhibition and underscores the need for site-specific modulation that preserves physiological tissue remodeling while suppressing pathological activity. Advances in precision medicine, single-cell and spatial transcriptomics, organoid-based disease models, and microbiome-informed therapeutic strategies are expected to facilitate the development of next-generation MMP-2-targeted interventions. Collectively, MMP-2 represents a promising yet complex therapeutic target whose successful modulation may improve long-term outcomes in IBD.