Danshensu sodium attenuates pyroptosis in ischemic stroke by targeting the HMGB1/RAGE axis and downstream NLRP3/GSDMD/ASC/Caspase-1 pathway

IF 3.6 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Cytokine Pub Date : 2026-03-01 Epub Date: 2026-01-10 DOI:10.1016/j.cyto.2026.157109

Jing Zhang , Dandan Liu , Chuanyu Jia , Shuyang Wang , Yuhui Li

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Abstract

Background

Danshensu Sodium (DSS-S), the sodium salt of a principal water-soluble active compound from Salvia miltiorrhiza, was investigated for its effects on cerebral ischemic-reperfusion (I/R) injury and the underlying molecular mechanisms.

Methods

Neuroprotection by DSS-S was evaluated in vivo using a transient middle cerebral artery occlusion (tMCAO) model in male C57BL/6J mice and in vitro using an oxygen-glucose deprivation/reperfusion (OGD/R) model in Neuro-2a mouse neuroblastoma cells.

Results

High-mobility group box 1 (HMGB1) was identified as a key target of DSS-S. Following I/R or OGD/R, levels of IL-1β, IL-6, TNF-α, IL-18, and HMGB1 were significantly elevated in both mouse serum and cell culture supernatant, and these increases were substantially attenuated by DSS-S treatment. DSS-S reduced cytoplasmic HMGB1 accumulation, promoted its nuclear retention, down-regulated the receptor for advanced glycation end-products (RAGE), and weakened the HMGB1-RAGE interaction. Pyroptosis was activated in both tMCAO and OGD/R models, and DSS-S intervention effectively inhibited pyroptosis by suppressing the HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation.

Conclusion

DSS-S exerts neuroprotective effects against cerebral I/R injury in vivo and reduces OGD/R-induced injury in vitro. The protection is mediated through inhibition of pyroptosis, achieved by targeting the HMGB1/RAGE axis and suppressing NLRP3 inflammasome activation.

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丹参素钠通过靶向HMGB1/RAGE轴和下游NLRP3/GSDMD/ASC/Caspase-1通路减轻缺血性脑卒中的焦亡

研究丹参素钠（DSS-S）作为丹参中主要水溶性活性化合物的钠盐对大鼠脑缺血再灌注（I/R）损伤的影响及其分子机制。方法在体内采用雄性C57BL/6J小鼠短暂性大脑中动脉闭塞（tMCAO）模型，在体外采用神经母细胞瘤细胞氧糖剥夺/再灌注（OGD/R）模型，评价DSS-S对神经的保护作用。结果高迁移率组框1 （HMGB1）被确定为DSS-S的关键靶点。在I/R或OGD/R后，小鼠血清和细胞培养上清中IL-1β、IL-6、TNF-α、IL-18和HMGB1的水平均显著升高，DSS-S处理后这些升高明显减弱。DSS-S减少细胞质HMGB1积累，促进其核保留，下调晚期糖基化终产物受体（RAGE），减弱HMGB1-RAGE相互作用。tMCAO和OGD/R模型均可激活焦亡，DSS-S干预通过抑制HMGB1/RAGE信号通路和NLRP3炎性体激活有效抑制焦亡。结论dss - s在体内对脑I/R损伤具有神经保护作用，在体外可减轻OGD/R损伤。这种保护是通过抑制焦亡介导的，通过靶向HMGB1/RAGE轴和抑制NLRP3炎性体的激活来实现。

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来源期刊

Cytokine 医学-免疫学

CiteScore

7.60

自引率

2.60%

发文量

262

审稿时长

48 days

期刊介绍： The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.