{"doi":"10.1101/2025.09.23.678172","title":"Repurpose of Ritlecitinib Reduces Neointima Formation and Enhances Endothelial Recovery Following Vascular Injury","abstract":"Background: Neointimal hyperplasia after vascular injury reflects excess smooth muscle cell (SMC) proliferation with impaired endothelial recovery. We tested the hypothesis that selective Janus kinase 3 (JAK3) inhibition with the FDA-approved drug Ritlecitinib limits neointima while accelerating reendothelialization. Methods: We used mouse carotid wire injury and a human internal mammary artery (IMA) xenograft model to evaluate effects of genetic JAK3 loss in SMCs or oral Ritlecitinib in vascular remodeling. Mechanistic studies in SMCs assessed JNK/c-Jun signaling and its regulation of thrombospondin-1 (TSP-1) and vascular endothelial growth factor A (VEGF-A) using RNA-seq and CUT&RUN. Rescue experiments tested whether VEGF-A neutralization or exogenous TSP-1 reversed the antineointimal effects. Patient-derived IMA SMCs were analyzed for variabilities in drug responses. Results: Genetic JAK3 loss in SMCs or oral Ritlecitinib reduced neointimal area and intima/media ratio and increased luminal CD31+ coverage in both models. In SMCs, Ritlecitinib suppressed JNK/c-Jun signaling, downregulated TSP-1, and restored VEGF-A, shifting the milieu toward endothelial regeneration. RNA-seq and CUT&RUN corroborated JNK/c-Jun- dependent control of TSP-1 and VEGFA. VEGF-A neutralization or exogenous TSP-1 abrogated the anti-neointimal phenotype. In patient-derived IMA SMCs, variable drug response was linked to the JAK3 Pro893Asn variant and a VEGFA promoter SNP. Conclusion: Selective JAK3 inhibition by Ritlecitinib simultaneously restrains SMC proliferation and promotes endothelial repair through modulating TSP-1 and VEGF-A activities. Ritlecitinib merits clinical evaluation as a precision therapy to prevent restenosis, with genetic stratification to identify responders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":576180,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9637,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":572233,"name":"Yung-Chun Wang","orcid":"0000-0002-8775-3472","position":1,"is_corresponding":false},{"id":1484762,"name":"Lindsey L. Saint","orcid":"0009-0008-0995-1319","position":2,"is_corresponding":false},{"id":1485147,"name":"John G. Markley","orcid":null,"position":3,"is_corresponding":false},{"id":248733,"name":"Shi‐You Chen","orcid":null,"position":4,"is_corresponding":false},{"id":247213,"name":"Dunpeng Cai","orcid":"0000-0002-0489-6567","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:57:56.636458Z","pmid":"41040305","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}