Cucurbitacin derivatives (B, IIa, IIb, and E): modulating gut dysbiosis and inflammatory pathways for multi-target therapy of ulcerative colitis.

Ulcerative colitis (UC) is a colon-associated inflammatory bowel disease (IBD) that extends from rectum to complete colon characterized by ulceration, rectal bleeding, bloody diarrhoea, and abdominal pain, epithelial barrier disruption, gut dysbiosis, immune dysregulation and recurrent mucosal inflammation. Today, several clinical medications such as corticosteroids, aminoslicylates and immuno-modulators are available, but each one of them have their own side effects. Therefore, to overcome these limitations, we are moving toward herbal drug therapies. This review presents the emerging role of Cucurbitacin (Cu), a highly oxygenated tetracyclic triterpenoid compound found in a variety of Cucurbitaceae plants and known for its anti-inflammatory response. Unlike previous reviews which just focuses on single derivatives or isolated mechanisms, this review focuses on multi-target analysis of Cucurbitacin (Cu) derivatives- CuB, CuE, CuIIa, and CuIIb, their biosynthesis, structure-activity relationships (SAR), inflammatory pathway modulation, gut microbiota regulation, extracellular vesicle-associated microRNAs, and differentially expressed genes (DEGs). The preclinical evidences shows that these derivatives of Cu have capability to treat UC, by inhibiting the Inflammatory pathways such as NLRP3 inflammasome, NF-κB, JAK2/STAT3, MAPK and EGFR, which results in decreasing the level of Inflammatory cytokines such as IL-6, IL-1β and TNF-α. They also upregulates the SCFAs producing beneficial bacteria and downregulates the harmful bacteria, thereby restoring epithelial integrity. Notably, Cu Ⅱa is associated with alteration in composition of protein and microRNA in extracellular vesicles. All these factors help in the treatment of UC. Although preclinical findings are encouraging, the current evidence is largely restricted to DSS induced animal models and the clinical validation in human is still lacking. Various challenges related to narrow therapeutic windows, poor bioavailability, and toxicity require resolution before clinical translation. This review find these translational gaps and proposes targeted research directions including nanoformulation strategies, pharmacokinetic profiling, and early-phase clinical evaluation.