Costunolide-Mediated Modulation of the P2X7-NLRP3 Complex Suppresses Oligodendrocyte Precursor Cell Pyroptosis and Rescues Perinatal White Matter Injury.

Abstract

BACKGROUND: Perinatal white matter injury (WMI) causes neurodevelopmental disability, driven by oligodendrocyte precursor cell (OPC) pyroptosis. We aimed to identify the molecular mechanism of NLRP3 inflammasome assembly in OPCs and evaluate Costunolide (Cos) as a targeted modulator of the P2X7-NLRP3 complex. METHODS: We integrated molecular dynamics simulations, surface plasmon resonance, primary OPC cultures, single-cell RNA sequencing, and a custom CRISPR/Cas9-generated P2rx7 knockout rat model to assess Cos efficacy. RESULTS: Cos associated with the extracellular domain of P2X7 (KD = 3.08 μM, Homo sapiens P2X7), modulating the P2X7-NLRP3 complex, thereby restricting calcium influx and preventing Caspase-1 activation and GSDMD-mediated membrane pore formation in vitro. Single-cell transcriptomic analysis identified an injury-induced P2rx7+/Nlrp3+ OPC subpopulation, revealing a previously unrecognized cell-intrinsic susceptibility to neuroinflammatory injury. Both genetic deletion of P2rx7 and pharmacological treatment with Cos markedly suppressed pyroptotic signaling in vivo, resulting in sustained restoration of myelin integrity and enhanced oligodendrocyte maturation from the acute (P7) to the developmental recovery (P14) stage. CONCLUSIONS: Our findings suggest that P2X7 may facilitate NLRP3 inflammasome assembly in developing OPCs. Consequently, modulation of this complex by Cos highlights a potential neurotherapeutic strategy for perinatal WMI.

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