Page 85 - JCTR-11-5

Journal of Clinical and

Translational Research

ORIGINAL ARTICLE
Comparative transcriptomic analysis of

macrophages treated with a combination of
ROCK pathway inhibitors

Arijita Subuddhi 1,2,3 , Marta Halasa , Ahmed Uosef 1,2 , Dawei Zou 1 ,
1,2
Souhail A. Thabet 2 , Henry V. Ubelaker , Rafik M. Ghobrial 1,2 , and
1,2
1,2
Malgorzata Kloc *
1 Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston,
Texas, United States of America
2 Department of Surgery, Houston Methodist Hospital, Houston, Texas, United States of America
3 Emory/GA Tuberculosis Research Advancement Center (TRAC), Emory Vaccine Center, Atlanta,
Georgia, United States of America

Abstract
*Corresponding author: Background: At present, there is no therapy for the long-term (chronic) rejection
Malgorzata Kloc of transplanted organs. This condition leads to tissue fibrosis and occlusion of the
(mkloc@houstonmethodist.org)
blood vessels. Aim: The overall goal of the current research is to identify a clinically
Citation: Subuddhi A, Halasa M, applicable therapy for chronic rejection in transplanted organs. Our previous
Uosef A, et al. Comparative
transcriptomic analysis of study showed that inhibitors of the RhoA/Rock pathway, such as Rezurock and
macrophages treated with a fingolimod, prevent chronic rejection in rodent transplantation models, with
combination of ROCK pathway Rezurock being superior in reducing fibrosis. Materials and methods: In this
inhibitors. J Clin Transl Res.
2025;11(5):79-95. study, we analyzed the effect of a Rezurock and fingolimod combination on the
doi: 10.36922/JCTR025270036 transcriptome of mouse peritoneal macrophages and protein expression in both
mouse and human macrophages. Results: The Rezurock/fingolimod combination
Received: July 4, 2025
resulted in the differential expression of 4,855 genes (2,477 downregulated and 2378
Revised: August 9, 2025 upregulated). Downregulated genes were related to fibrotic pathways, extracellular
Accepted: August 15, 2025 matrix, blood vessel development, cell adhesion, and cytokine production. Protein
expression analysis showed that Rezurock/fingolimod treatment had a significantly
Published online: October 14,
2025 stronger effect on the expression of pentraxin 3, chemokine (C-C motif) ligand 2,
C-C motif chemokine receptor 2, and transforming growth factor beta 1 in mouse
Copyright: © 2025 Author(s).
This is an open-access article macrophages, and was much more effective in reducing the expression of Notch1
distributed under the terms of the and Rho-associated coiled-coil kinase 2 in human macrophages compared to
Creative Commons AttributionNon- individual treatments. Conclusion: Rezurock/fingolimod treatment not only affects
Commercial 4.0 International (CC
BY-NC 4.0), which permits all fibrotic pathways but also downregulates genes related to cell cycle progression and
non-commercial use, distribution, cytokine production and disrupts macrophage recruitment signaling. These findings
and reproduction in any medium, indicate that Rezurock, alone or in combination with other immunomodulators, may
provided the original work is
properly cited. be a promising candidate for clinical therapy targeting chronic rejection.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Rezurock; Fibrosis; Chronic rejection; Macrophage; Ras homolog family
regard to jurisdictional claims in
published maps and institutional member A/Rho-associated coiled-coil kinase pathway
affiliations.

Volume 11 Issue 5 (2025) 79 doi: 10.36922/JCTR025270036