ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway

Tianru Huyan1,2, Lu Fan1,3, Zhong-yuan Zheng1, Jing-hui Zhao2, Zhen-ru Han1,3, Pin Wu1, Qun Ma1, Ya-qin Du1, Yun-di Shi1, Chun-yan Gu3, Xue-jun Li1, Wen-hui Wang4, Long Zhang2, Lu Tie1
1 Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China
2 Department of Wound Healing Center and Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing 100191, China
3 School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
4 Department of Dermatology, Peking University Third Hospital, Beijing 100191, China
Correspondence to: Long Zhang:, Lu Tie:,
DOI: 10.1038/s41401-024-01246-3
Received: 4 October 2023
Accepted: 19 February 2024
Advance online: 27 March 2024


Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

Keywords: ROCK1; wound; diabetes; mitochondria; AMPK

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