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Background <p>Necrotizing enterocolitis (NEC) is a life-threatening intestinal inflammatory disease in preterm infants. Inositol hexakisphosphate kinase 1 (IP6K1) regulates platelet polyphosphate (polyP) homeostasis, yet its roles in NEC remain unclear.</p> Objective <p>This study aimed to investigate the regulatory mechanism of platelet IP6K1 in neutrophil-platelet aggregate (NPA) formation and NEC pathogenesis, and to evaluate the therapeutic potential of IP6K1 inhibition.</p> Methods <p>Clinical samples from patients with NEC were analyzed to assess circulating mitochondrial DNA, anticardiolipin IgG levels, platelet alterations, platelet cell death patterns, and NPA formation. A mouse model of NEC was used to evaluate the effects of genetic IP6K1 deficiency and pharmacological IP6K inhibition with TNP on survival, intestinal injury, neutrophil infiltration, neutrophil extracellular trap (NET) formation, and inflammatory responses. Mechanistic experiments were performed using exogenous polyP supplementation and P-selectin neutralization</p> Results <p>Patients with NEC exhibited significantly increased circulating mitochondrial DNA levels, elevated anticardiolipin IgG levels, enhanced NPA formation, reduced platelet counts, abnormal platelet morphological parameters, and platelet pyroptosis as the predominant mode of cell death. In NEC mice, both IP6K1 deficiency and TNP treatment improved survival, preserved intestinal mucosal architecture, reduced disease severity, and markedly attenuated neutrophil infiltration and NET formation. Mechanistically, IP6K1 promoted NPA formation and downstream inflammatory responses by regulating the release of platelet-derived short-chain polyP. Exogenous polyP supplementation restored the impaired NPA formation observed in IP6K1⁻/⁻ mice. Moreover, P-selectin neutralization suppressed NPA formation and reduced NET production in inflamed intestinal tissues.</p> Conclusion <p>Platelet IP6K1 is a key regulator of NPA formation and NET release in NEC through its control of platelet-derived short-chain polyP. Targeting IP6K1 may represent a promising therapeutic strategy for mitigating local and systemic inflammation in severe NEC.</p>

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Inhibition of IP6K1 suppresses NPA formation via platelet short-chain polyphosphate polymers in necrotizing enterocolitis

  • 期刊论文

  • 发表日期：

    2026年6月20日

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  • Kai Gao,
  • Muyang Zhu,
  • Qianyang Liu,
  • Yue Ma,
  • Hongmei Xu,
  • Chunbao Guo

摘要

Background

Necrotizing enterocolitis (NEC) is a life-threatening intestinal inflammatory disease in preterm infants. Inositol hexakisphosphate kinase 1 (IP6K1) regulates platelet polyphosphate (polyP) homeostasis, yet its roles in NEC remain unclear.

Objective

This study aimed to investigate the regulatory mechanism of platelet IP6K1 in neutrophil-platelet aggregate (NPA) formation and NEC pathogenesis, and to evaluate the therapeutic potential of IP6K1 inhibition.

Methods

Clinical samples from patients with NEC were analyzed to assess circulating mitochondrial DNA, anticardiolipin IgG levels, platelet alterations, platelet cell death patterns, and NPA formation. A mouse model of NEC was used to evaluate the effects of genetic IP6K1 deficiency and pharmacological IP6K inhibition with TNP on survival, intestinal injury, neutrophil infiltration, neutrophil extracellular trap (NET) formation, and inflammatory responses. Mechanistic experiments were performed using exogenous polyP supplementation and P-selectin neutralization

Results

Patients with NEC exhibited significantly increased circulating mitochondrial DNA levels, elevated anticardiolipin IgG levels, enhanced NPA formation, reduced platelet counts, abnormal platelet morphological parameters, and platelet pyroptosis as the predominant mode of cell death. In NEC mice, both IP6K1 deficiency and TNP treatment improved survival, preserved intestinal mucosal architecture, reduced disease severity, and markedly attenuated neutrophil infiltration and NET formation. Mechanistically, IP6K1 promoted NPA formation and downstream inflammatory responses by regulating the release of platelet-derived short-chain polyP. Exogenous polyP supplementation restored the impaired NPA formation observed in IP6K1⁻/⁻ mice. Moreover, P-selectin neutralization suppressed NPA formation and reduced NET production in inflamed intestinal tissues.

Conclusion

Platelet IP6K1 is a key regulator of NPA formation and NET release in NEC through its control of platelet-derived short-chain polyP. Targeting IP6K1 may represent a promising therapeutic strategy for mitigating local and systemic inflammation in severe NEC.