Inhibition of IP6K1 Suppresses NPC Formation via Platelet Short-Chain Polyphosphate Polymers in Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a life-threatening intestinal inflammatory disease in preterm infants. Inositol hexakisphosphate kinase 1 (IP6K1) regulates platelet polyphosphate (polyP) homeostasis, yet their roles in NEC remain unclear. This study aimed to investigate the regulatory mechanism of platelet IP6K1 in neutrophil-platelet aggregate (NPA) formation and NEC pathogenesis, as well as the therapeutic potential of IP6K1 inhibition. Clinical analyses revealed significantly elevated circulating mitochondrial levels, anticardiolipin IgG concentrations and NPAs in NEC patients. Platelets in NEC patients exhibited reduced counts, abnormal morphological parameters and pyroptosis as the primary cell death mode. In the mouse NEC model, LPS-induced NPA formation, neutrophil infiltration and neutrophil extracellular trap (NET) release were significantly attenuated in IP6K1⁻/⁻ mice and TNP-treated mice. IP6K1 deficiency and TNP treatment significantly improved the survival rate of NEC mice, ameliorated intestinal mucosal structural damage, reduced disease severity scores. Mechanistically, IP6K1 regulated NPA formation and subsequent inflammatory responses by mediating platelet short-chain polyP secretion, and exogenous polyP supplementation could rescue the impaired NPA formation in IP6K1⁻/⁻ mice. P-selectin neutralization not only inhibited NPA formation but also reduced NET production in inflamed intestinal tissues. In conclusion, platelet IP6K1 promotes NPA formation and NET release as a novel critical regulator of NEC pathogenesis and a promising therapeutic target for attenuating local and systemic inflammation in severe NEC.