Cyclosporin a directly binds CCL5: a novel mechanism in SJS/TEN revealed by network pharmacology
- 1Department of Dermatology, Nanchang University Second Affiliated Hospital
- 2Department of Health Toxicology, School of Public Health, Shanxi Medical University
Abstract
Background: Stevens-Johnson syndrome/toxic epidermal necrolysis, the most acute and severe of severe cutaneous adverse reactions, has an annual incidence of 0.4–13 cases per million and mortality rates range from <10% in Stevens-Johnson syndrome to >40% in toxic epidermal necrolysis, with an overall mortality of approximately 20%. Cyclosporin A (CsA) is clinically effective in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), but its mechanism beyond calcineurin inhibition remains unclear.
Objectives: To identify novel therapeutic targets of CsA in SJS/TEN using network pharmacology and validate the most promising candidate experimentally.
Methods: Potential CsA targets were predicted using PharmMapper and SuperPred. SJS/TEN-associated genes were retrieved from GeneCards and OMIM. Common targets were analyzed via protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment. Molecular docking predicted binding modes. The key target interaction was validated in vitro using MicroScale Thermophoresis.
Results: We identified 22 shared targets between CsA and SJS/TEN. Network analysis highlighted five core proteins (MMP9, CASP3, CCL5, CXCR4, CYP3A4). Molecular docking predicted stable binding between CsA and Chemokine (C-C motif) ligand 5 (CCL5). Critically, MST assays demonstrated direct physical interaction between CsA and CCL5 protein with a dissociation constant (Kd) of 2.7 μM.
Conclusion: In conclusion, our in vitro experiments confirmed a direct physical binding interaction between CsA and the key chemokine CCL5, providing a novel potential mechanistic hypothesis for the rapid anti-inflammatory effect of CsA in SJS/TEN. However, this hypothesis requires validation through cell-based chemotaxis assays.
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BibTeX
@article{peng2026cyclosporin,
title = {{Cyclosporin a directly binds CCL5: a novel mechanism in SJS/TEN revealed by network pharmacology}},
author = {Fangqin Peng and Wenjie Hao and Yating Peng and Ougen Liu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1853184},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1853184/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cyclosporin a directly binds CCL5: a novel mechanism in SJS/TEN revealed by network pharmacology
AU - Fangqin Peng
AU - Wenjie Hao
AU - Yating Peng
AU - Ougen Liu
PY - 2026
DA - 2026/10/21
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1853184
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1853184/full
AB - Background: Stevens-Johnson syndrome/toxic epidermal necrolysis, the most acute and severe of severe cutaneous adverse reactions, has an annual incidence of 0.4–13 cases per million and mortality rates range from <10% in Stevens-Johnson syndrome to >40% in toxic epidermal necrolysis, with an overall mortality of approximately 20%. Cyclosporin A (CsA) is clinically effective in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), but its mechanism beyond calcineurin inhibition remains unclear. Objectives: To identify novel therapeutic targets of CsA in SJS/TEN using network pharmacology and validate the most promising candidate experimentally. Methods: Potential CsA targets were predicted using PharmMapper and SuperPred. SJS/TEN-associated genes were retrieved from GeneCards and OMIM. Common targets were analyzed via protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment. Molecular docking predicted binding modes. The key target interaction was validated in vitro using MicroScale Thermophoresis. Results: We identified 22 shared targets between CsA and SJS/TEN. Network analysis highlighted five core proteins (MMP9, CASP3, CCL5, CXCR4, CYP3A4). Molecular docking predicted stable binding between CsA and Chemokine (C-C motif) ligand 5 (CCL5). Critically, MST assays demonstrated direct physical interaction between CsA and CCL5 protein with a dissociation constant (Kd) of 2.7 μM. Conclusion: In conclusion, our in vitro experiments confirmed a direct physical binding interaction between CsA and the key chemokine CCL5, providing a novel potential mechanistic hypothesis for the rapid anti-inflammatory effect of CsA in SJS/TEN. However, this hypothesis requires validation through cell-based chemotaxis assays.
SN - 1663-9812
ER -