Sinapine thiocyanate (ST) ameliorates endothelial cell dysfunction by targeting chloride intracellular channel 4 (CLIC4) to treat hypoxia-induced pulmonary hypertension

  • Br J Pharmacol. 2026 Sep 30. doi: 10.1111/bph.70676.
Xiaowei Gong  1 ,  Yuming Wang  2 ,  Shiwei Kang  1 ,  Ziping Zhang  1 ,  Xin Liu  1 ,  Weibo Wen  3 ,  Yanling Sheng  4 ,  Yadong Yuan  1 ,  Huantian Cui  3 ,  Feitian Min  3
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • 2. School of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 3. First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China.
  • 4. Department of Respiratory and Critical Care Medicine, North China Petroleum Administration Bureau General Hospital, Renqiu, China.
PMID: 42817595 DOI: 10.1111/bph.70676
Abstract

Background and purpose: Sinapine thiocyanate (ST) has effects in treating respiratory diseases. Its action in hypoxic Pulmonary Hypertension (HPH) remains poorly understood. We evaluated the potential of ST on HPH and its molecular mechanism.

Experimental approach: ST was evaluated on a rat model HPH. Single-cell RNA Sequencing (scRNA-seq) identified ST-modulated cell clusters. ST regulation on endothelial dysfunction-induced neutrophil migration in vivo and in vitro was studied. Molecular docking, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) analysis were used to identify targets of ST. The molecular mechanism by which ST modulates endothelial cell dysfunction through gene silencing experiments was also investigated.

Key results: ST significantly reduced pulmonary arterial pressure in HPH rats and alleviated pathological changes in lung tissue. scRNA-seq showed that ST markedly decreased the proportion of neutrophils, down-regulated the expression of their cell migration-related genes and the gene expression of chemokines in endothelial cells. In vivo experimental indicated that ST reduced neutrophil infiltration in lung tissue and lowered inflammatory cytokine levels in bronchoalveolar lavage fluid. Further in vitro studies indicated that ST reduced neutrophil migration by inhibiting hypoxia-induced endothelial dysfunction. ST inhibited P65 phosphorylation-mediated endothelial dysfunction by targeting chloride intracellular channel 4 (CLIC4). Inhibiting CLIC4 activation through blocking the cascade reaction of CLIC4 up-regulation and activation induced by pro-inflammatory cytokines. Silencing endothelial cell CLIC4 abolishes ST inhibitory effects on inflammatory cytokine expression and regulatory impact on P65 activation.

Conclusions and implications: ST targeted CLIC4 inhibits NF-κB p65 activation would have therapeutic effects against HPH.

Keywords
chloride intracellular channel 4; endothelial cell dysfunction; hypoxic pulmonary hypertension.
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