Novel Small-Molecule miR-124 Inducer Acts as "a Physiological Brake" of Inflammation in Ulcerative Colitis by Targeting the PIK3R2/PI3K/Akt Axis.

Ulcerative colitis (UC), a chronic inflammatory bowel disease with limited therapeutic options, necessitates novel treatments targeting its complex pathophysiology. This study identified FHND5032, a novel small-molecule miR-124 inducer, as a potent therapeutic candidate for UC. We found that FHND5032 significantly upregulated miR-124 expression in macrophages, surpassing the clinical-stage comparator ABX464 in vitro and in vivo. Mechanistically, miR-124-5p directly targeted PIK3R2, suppressing the PI3K/Akt pathway and decreasing proinflammatory cytokines while promoting M2 macrophage polarization. In dextran sodium sulfate-induced mouse colitis, FHND5032 markedly reduced the disease activity index, restored colon length, preserved mucosal architecture, and repaired intestinal barrier integrity. Additionally, FHND5032 reversed gut dysbiosis by reducing Proteobacteria and enriching beneficial Firmicutes, outperforming ABX464 in microbiome modulation. Safety assessments confirmed no organ toxicity or biochemical abnormalities. Collectively, FHND5032 exerted multifaceted anticolitis effects by targeting the PIK3R2/PI3K/Akt axis, restoring immune homeostasis, and modulating gut microbiota, positioning it as a promising therapeutic agent for UC.