Pumpkin Polysaccharide Ameliorates Type 2 Diabetes in Mice via Inhibition of p38 MAPK, Activation of PINK1‐PRKN Mitophagy, and Gut Microbiota Modulation

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose and lipid metabolism and gut microbiota dysbiosis. This study investigated the therapeutic potential and mechanisms of pumpkin polysaccharide fraction 3 (PPS3), a pumpkin polysaccharide, in a T2DM mouse model. Results demonstrated that PPS3 administration significantly increased body weight, reduced fasting blood glucose, attenuated hyperphagia and polydipsia, and enhanced glucose tolerance and insulin sensitivity. Hepatic analyses showed that PPS3 promoted glycogen synthesis and upregulated key glycolytic enzymes, hexokinase, and pyruvate kinase, contributing to restored glucose homeostasis. Mechanistically, PPS3 inhibited p38 mitogen-activated protein kinase (p38 MAPK) signaling and activated PTEN-induced kinase 1 (PINK1)-Parkin (PRKN)-mediated mitophagy, enhancing mitochondrial quality control. Gut microbiota analysis showed that PPS3 reduced the Firmicutes/Bacteroidota ratio and pathogenic genera while enriching beneficial bacteria including Akkermansia and short-chain fatty acid (SCFA) producers. Fecal metabolomics revealed partial restoration of metabolic disturbances, notably increased levels of propionyl-l-carnitine, indole-3-lactic acid, and β-lapachone. PPS3 exerted multifaceted metabolic benefits via inhibition of p38 MAPK, activation of PINK1-PRKN mitophagy, and gut microbiota modulation, positioning it as a promising candidate for T2DM intervention.