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Publications

Journal Article Epublish

PubMed: 40744980 DOI: 10.1038/s41598-025-13187-w

Integrative network pharmacology and multi-omics reveal anisodamine hydrobromide's multi-target mechanisms in sepsis.

Sci Rep 15(1):27996

Authors: Ying Chen, Danlei Weng, Wei Shi, Shuxing Wei, Wenqing Ji, Xiya Wang, Yali Xu, Xiaoman Wang, Xue Mei, Shubin Guo

Affiliations

  • Emergency Medicine Clinical Research Center, Beijing Key Laboratory of Cardiopulmonar Cerebral Resuscitation, Beijing Chaoyang Hospital, Affiliated to Capital Medical University, Beijing, 100020, China. National Institute for Data Science in Health and Medicine, Capital Medical University, Beijing, 100069, China.
  • Emergency Medicine Clinical Research Center, Beijing Key Laboratory of Cardiopulmonar Cerebral Resuscitation, Beijing Chaoyang Hospital, Affiliated to Capital Medical University, Beijing, 100020, China.
  • Department of Rehabilitation, Shenzhen Dapeng New District Nan'ao People's Hospital, Shenzhen, 518121, China.
  • Emergency Medicine Clinical Research Center, Beijing Key Laboratory of Cardiopulmonar Cerebral Resuscitation, Beijing Chaoyang Hospital, Affiliated to Capital Medical University, Beijing, 100020, China.
  • Emergency Medicine Clinical Research Center, Beijing Key Laboratory of Cardiopulmonar Cerebral Resuscitation, Beijing Chaoyang Hospital, Affiliated to Capital Medical University, Beijing, 100020, China.

Abstract

Sepsis, marked by hyperinflammation and subsequent immunosuppression, lacks effective phase-specific therapies. Although anisodamine hydrobromide (Ani HBr) reduced 28-day mortality in our prior trial, its mechanisms remained unclear. Here, we integrated network pharmacology, machine learning, immunological profiling, molecular simulations, and single-cell transcriptomics to elucidate Ani HBr's multi-target actions. Among 30 cross-species targets, ELANE and CCL5 emerged as core regulators via protein interaction networks, survival modeling (AUC: 0.72-0.95), and statistical significance (p < 0.05). Ani HBr inhibited ELANE-driven NET formation (HR = 1.176), associated with immunosuppression and endothelial damage, while enhancing CCL5-related cytotoxic T-cell recruitment (HR = 0.810). Docking and dynamics simulations showed Ani HBr binds ELANE's catalytic cleft, suggesting direct inhibition of its enzymatic activity, and interacts stably with CCL5 at potential receptor-binding interfaces, indicating a modulatory role. Single-cell analysis revealed ELANE upregulation in CCI-phase neutrophils and widespread yet stage-specific CCL5 expression. These findings support Ani HBr as a phase-tailored agent that targets ELANE in early hyperinflammation while preserving CCL5-mediated immunity. The ELANE/CCL5 prognostic model offers a framework for precision immunotherapy in sepsis.

MeSH

Cells, Multiple Chronic Conditions, Sepsis, Pharmacology, Immunosuppression Therapy