Puerarin attenuates inflammatory progression in atherosclerosis by inhibiting NLRP3 inflammasome activation via the SphK1/S1P/S1PR1 axis

Objective Atherosclerosis (AS) is a chronic inflammatory cardiovascular disease. The sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling axis plays a key role in inflammation regulation, but its precise role in AS pathogenesis remains unclear. Puerarin (Pue), an isoflavone derived from the medicinal and dietary plant Pueraria lobata , exhibits cardiovascular protective effects, though its pharmacological mechanisms remain to be elucidated. This study aimed to investigate the involvement of the SphK1/S1P/S1P receptor (S1PRs) pathway in AS progression and to evaluate the therapeutic effects of Pue. Methods ApoE −/− and SphK1 −/− mice were bred to generate ApoE −/− SphK1 −/− mice. C57BL/6J, ApoE −/− , SphK1 −/− , and ApoE −/− SphK1 −/− mice were fed a high-fat diet to induce atherosclerosis and evaluate the effects of SphK1 deficiency. High-fat diet-induced ApoE −/− mice received oral administration of Pue at low and high doses to assess its therapeutic effects. AS progression was evaluated by monitoring serum biochemical parameters, performing histological analyses (H&E staining, Oil Red O staining, Masson's trichrome, and Von Kossa staining), and detecting the expression of S1PR1 and NLRP3 inflammasome-related proteins (NLRP3, Caspase-1, ASC) in aortic tissues to systematically assess the effects of SphK1 deficiency and Pue intervention on the SphK1/S1P/S1PR1/NLRP3 signaling pathway. Results Both SphK1 deficiency and Pue treatment significantly attenuated AS progression, as evidenced by improved lipid profiles, reduced systemic inflammation, decreased atherosclerotic plaque formation, and improved vascular structure. Mechanistic analysis indicated that SphK1 deficiency or Pue intervention reduced serum S1P levels and downregulated the expression of S1PR1 and NLRP3 inflammasome-related proteins in aortic tissues, suggesting that the effect is likely mediated through inhibition of the S1P/S1PR1/NLRP3 signaling axis. Conclusion Genetic ablation of SphK1 or Pue intervention mitigates AS through suppression of the S1P/S1PR1/NLRP3 inflammasome pathway. This study provides novel mechanistic insights into the role of SphK1/S1P/S1PR1 signaling in vascular inflammation and highlights Pue as a potential therapeutic strategy for AS.