Work

Cyclosporin a directly binds CCL5: a novel mechanism in SJS/TEN revealed by network pharmacology

Year: 2026

Type: article

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.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1853184

Authors: Fangqin Peng, Wenjie Hao, Yating Peng, Ougen Liu

Institutions: Nanchang University, Second Affiliated Hospital of Nanchang University, Shanxi Medical University

Language: English

Topic: Drug-Induced Adverse Reactions

Subfield: Pharmacology (medical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801