PirB Inhibition Mitigates Neonatal White Matter Injury via Regulating Nlrp3-Driven PANoptosis in Oligodendrocyte Precursor Cells

Abstract Background: White matter injury (WMI) is a major cause of neurological impairment in preterm infants, characterized by demyelination due to disrupted oligodendrocyte precursor cell (OPC) maturation. Currently, no effective treatment exists. This study investigates the role of paired immunoglobulin-like receptor B (PirB) and the novel programmed cell death pathway—pan-apoptosis (PANoptosis)—in the pathogenesis of WMI. Methods: A neonatal rat model of WMI was established via intracerebroventricular injection of lipopolysaccharide (LPS). PirB expression was modulated using the inhibitor Fluspirilene or siRNA-mediated silencing. The NLRP3 inhibitor MCC950 was employed to assess its role in PANoptosis. Histopathological changes were evaluated by H&E staining and transmission electron microscopy; myelin integrity and cell death were assessed via immunofluorescence and Western blotting. Mitochondrial DNA (mtDNA) release and NLRP3 interaction were visualized using confocal microscopy. Results: PirB was significantly upregulated in OPCs following WMI. Silencing PirB or inhibiting it with Fluspirilene reduced demyelination and white matter damage, decreased inflammation (IL-18 and TNF-α), and attenuated PANoptosis—simultaneously suppressing apoptosis, pyroptosis, and necroptosis. Mechanistically, PirB activation promoted mtDNA release into the cytoplasm via the Bax/Bak pathway, leading to NLRP3 inflammasome assembly and PANoptosome formation. Inhibition of NLRP3 with MCC950 similarly reduced all three forms of OPC death. Conclusions: PirB contributes to WMI by activating NLRP3-mediated PANoptosis in OPCs, leading to impaired myelination. Targeting the PirB/NLRP3 signaling axis may represent a promising therapeutic strategy for mitigating WMI in preterm infants.