Dnmt1 Alleviates S1PR1‐Mediated Pyroptosis after Spinal Cord Injury through Regulating Pon3 Expression

Abstract Spinal cord injury (SCI), as a severe neurological disorder, remains a formidable challenge in clinical treatment. Pyroptosis‐triggered neuroinflammation exacerbates secondary damage, neuronal death, and impairs recovery after SCI, making it a critical pathological factor. However, the exact pathophysiological mechanisms are incompletely understood. In this study, bioinformatics tools are first employed to identify key targets associated with SCI. Subsequent western blot and immunofluorescence assays reveal a time‐dependent decrease in Pon3 expression, which is predominantly localized in neuronal cells. Conversely, Dnmt1 expression shows a progressive increase following SCI. By constructing a Pon3‐overexpressing virus, it is demonstrated that Pon3 overexpression mitigates pyroptosis in rat and PC12 cells. This process promotes autophagy, significantly improving the prognosis of SCI in rats. Moreover, it enhances the survival rate of PC12 cells. mRNA sequencing and follow‐up experiments revealed that Pon3 inhibits the downstream target S1PR1, promotes autophagy, and thereby suppresses pyroptosis. Additionally, through the use of a Dnmt1 inhibitor and the knockout of the Pon3 gene, it is shown that Dnmt1 alleviates SCI‐induced pyroptosis by modulating Pon3 expression. Collectively, this work reveals that Dnmt1 alleviates S1PR1‐mediated pyroptosis following SCI via regulating Pon3 expression.