IITZ01 attenuates fructose aggravated ulcerative colitis via prevention of macrophage activation and decrease in cytokine release via inhibition of PIP5 kinase

Excessive dietary fructose intake is gradually recognised to exacerbate intestinal inflammation in Ulcerative Colitis (UC) through disruption of epithelial barrier integrity and microbial dysbiosis, resulting in hyper immune activation. Inflammation in UC is generally linked with PI3K/Akt/mTOR pathway activation; however, the underlying molecular mechanisms behind fructose-mediated immune hyper-activation remains incompletely understood. Hence, this study is aimed to investigate the role of phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks), a probable upstream regulator of PI3K, in high-fructose diet-induced colonic inflammation. In vitro and in vivo models of high fructose exposure were employed to evaluate the expression and functional role of PIP5Ks through pharmacological inhibition using ISA 2011B (PIP5K1A inhibitor) and IITZ01 (PIP5K1B inhibitor). Inflammatory responses, epithelial integrity, and disease severity were assessed using molecular, histological, and clinical indices in the high fructose + DSS induced UC in rodent model. High fructose exposure enhanced PIP5K expression, leading to increased levels of phosphatidylinositol 4,5-bisphosphate (PIP2), a key substrate for PI3K. This activation triggered downstream signalling that amplified inflammatory responses and compromised epithelial barrier function. Inhibition of PIP5Ks markedly attenuated fructose-induced inflammation in both cellular and animal models. Notably, IITZ01 demonstrated superior efficacy compared to ISA 2011B, as evidenced by improved disease activity index, restored epithelial structure, and reduced inflammatory burden. Collectively, our findings identify PIP5Ks as a critical mediator of fructose-induced intestinal inflammation and establish the PIP5K-PI3K signalling axis as a key regulator of macrophage activation and epithelial dysfunction. Targeting PIP5Ks may represent a promising therapeutic strategy for the management of UC.

Colitis; Dietary-fructose; Macrophage activation; PIP5K.