Ginsenoside Rh1 ameliorates polystyrene nanoplastics-caused vascular injury by regulating HSP70 to suppress endoplasmic reticulum stress and pyroptosis

INTRODUCTION: The vascular toxicity of polystyrene nanoparticles (PS-Nps) via the circulatory system has emerged as novel critical health risk factors. However, the specific mechanisms underlying PS-Nps-induced vascular endothelial injury and corresponding protective strategies remain poorly understood. OBJECTIVES: This work seeks to assess the vascular toxicity of PS-Nps and the function and mechanism of rare ginsenoside Rh1 derived from ginseng in alleviating vascular endothelial injury caused by PS-Nps. METHODS: To dissect the protective mechanisms of Rh1 against PS-Nps-triggered vascular endothelial injury across in vitro and in vivo models, we employed an integrated approach including western blot, immunofluorescence, histopathological staining, siRNA-mediated gene silencing, molecular docking, molecular dynamics simulations, co-immunoprecipitation (Co-IP), surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). Furthermore, transcriptome sequencing (RNA-seq) was performed to validate the key regulatory pathways involved. RESULTS: Rh1 inhibited the caspase-1-dependent pyroptosis pathway and NLRP3 inflammasome activation. Importantly, Rh1 exerted its endothelial protective effects by targeting HSP70, thereby suppressing NF-κB p65 nuclear translocation and downregulating endoplasmic reticulum stress (ERS) signaling via GRP78-ATF4-CHOP. Moreover, we further verified that Rh1 effectively alleviates atherosclerosis, reinforcing its translational value in classical cardiovascular disease settings. CONCLUSION: This research provides the first comprehensive investigation of the protective efficacy of ginsenoside Rh1 for preventing cardiovascular damage induced by the new environmental pollutant PS-Nps. This study provides an innovative theoretical basis for the prevention of cardiovascular diseases related to environmental pollutants by ginseng.