A comprehensive review of small molecules, targets, and pathways in ulcerative colitis treatment

Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), poses significant clinical challenges because of its complex pathophysiology, long-term nature, and the limited efficacy of existing treatments. Small-molecule compounds, particularly those that are able to modulate inflammation-related signaling pathways and, in many cases, occur in nature, offer a promising alternative or supplement to conventional therapies. Studies on molecules for UC therapeutics reported in 1394 publications over the past 30 years were collected from the Web of Science (WOS) database. Only studies that verified therapeutic efficacy through animal experiments were included. Through an analysis of the molecular classes, structures, common targets, and pathways using network pharmacology, we identified 14 classes of compounds, 5 direct-target modules, and 3 crucial downstream pathways. Alkaloids, phenylpropanoids, flavonoids, and terpenes (and their derivatives) appeared most frequently and mainly targeted lipid metabolism, oxidative stress, immune regulation, signaling transduction, and cancer-related pathways. Notably, there has been an increasing trend of applying naturally sourced compounds in both preclinical and clinical trials, especially flavonoids, over the last five years. Although progress in UC research has been made, the majority of studies have focused on the overall therapeutic effects and biomarker alterations, with limited emphasis on the direct targets and underlying mechanisms. These findings highlight the need to explore novel small-molecule therapeutic strategies for UC, focusing on clearly defined targets and precise modes of action.