Identification of the miR-210-3p-EFNA3-YAP axis and its targeted modulation via biomimetic supramolecular nanoparticles to promote ischemic flap survival.
12 affiliations
- 1Department of Orthopaedics, Yongkang First People's Hospital of Wenzhou Medical University, Jinhua, 321300, Zhejiang, China.
- 2Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- 3Department of Wound healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- 4Department of Radiology, Ruian Hospital Affiliated to Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- 5The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- 6The Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. [email protected].
- 7Department of Orthopaedics, Yongkang First People's Hospital of Wenzhou Medical University, Jinhua, 321300, Zhejiang, China. [email protected].
- 8Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. [email protected].
- 9Department of Wound healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. [email protected].
- 10Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. [email protected].
- 11Department of Wound healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. [email protected].
- 12Department of Orthopaedics, Yongkang First People's Hospital of Wenzhou Medical University, Jinhua, 321300, Zhejiang, China. [email protected].
Abstract
Ischemic skin flaps are highly susceptible to distal necrosis because of insufficient perfusion, oxidative stress, and dysregulated cell death. Here, we investigated the role of Hippo/YAP signaling in ischemic flap survival and identified its upstream regulatory mechanism. Hippo pathway inactivation, characterized by reduced MST1/2 and LATS1/2 phosphorylation and enhanced YAP nuclear localization, was preferentially associated with viable flap regions. Mechanistically, ischemia-induced HIF-1α upregulated miR-210-3p, which suppressed ephrin-A3 (EFNA3), weakened the EFNA3-YAP interaction, and promoted YAP nuclear translocation. Re-expression of EFNA3 partially reversed miR-210-3p-induced YAP activation and cytoprotection, confirming its functional involvement. Mechanistically, ischemia-induced HIF-1α increased miR-210-3p expression, which suppressed EFNA3 and facilitated YAP nuclear localization. EFNA3 re-expression partially reversed miR-210-3p-induced YAP activation, supporting its functional involvement. MiR-210-3p treatment was further associated with reduced oxidative injury, lipid peroxidation, mitochondrial dysfunction, and ferroptosis-related molecular alterations, together with improved perfusion and flap survival. In vivo, miR-210-3p improved local perfusion and flap survival. We further developed a virus-inspired biomimetic nanoparticle for miR-210-3p delivery, which achieved protective effects comparable to AAV-mediated delivery in vitro and in vivo. These findings identify the miR-210-3p-EFNA3-YAP axis as an important regulator of ischemic tissue adaptation and provide a non-viral miRNA delivery strategy for ischemic flap repair.
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BibTeX
@article{xu2026identification,
title = {{Identification of the miR-210-3p-EFNA3-YAP axis and its targeted modulation via biomimetic supramolecular nanoparticles to promote ischemic flap survival.}},
author = {Jie Xu and Xiuxiu Zhuang and Zichang Wu and Fuyi Yan and Deen Shi and Fan Ye and Ruihua Ding and Qi Gao and Qimin Yao and Yiying Liu and Xiaoyu Dong and Fan Zhang and Binbiao Li and Xiangwei Xu and Hongfei Tong and Yanzhi Yao and Wenbing Jiang and Jian Xiao and Zhenglin Li and Wei Chen},
journal = {Journal of nanobiotechnology},
year = {2026},
month = jul,
doi = {10.1186/s12951-026-04833-0},
url = {https://europepmc.org/article/MED/42907899},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Identification of the miR-210-3p-EFNA3-YAP axis and its targeted modulation via biomimetic supramolecular nanoparticles to promote ischemic flap survival.
AU - Jie Xu
AU - Xiuxiu Zhuang
AU - Zichang Wu
AU - Fuyi Yan
AU - Deen Shi
AU - Fan Ye
AU - Ruihua Ding
AU - Qi Gao
AU - Qimin Yao
AU - Yiying Liu
AU - Xiaoyu Dong
AU - Fan Zhang
AU - Binbiao Li
AU - Xiangwei Xu
AU - Hongfei Tong
AU - Yanzhi Yao
AU - Wenbing Jiang
AU - Jian Xiao
AU - Zhenglin Li
AU - Wei Chen
PY - 2026
DA - 2026/07/01
JO - Journal of nanobiotechnology
DO - 10.1186/s12951-026-04833-0
UR - https://europepmc.org/article/MED/42907899
AB - Ischemic skin flaps are highly susceptible to distal necrosis because of insufficient perfusion, oxidative stress, and dysregulated cell death. Here, we investigated the role of Hippo/YAP signaling in ischemic flap survival and identified its upstream regulatory mechanism. Hippo pathway inactivation, characterized by reduced MST1/2 and LATS1/2 phosphorylation and enhanced YAP nuclear localization, was preferentially associated with viable flap regions. Mechanistically, ischemia-induced HIF-1α upregulated miR-210-3p, which suppressed ephrin-A3 (EFNA3), weakened the EFNA3-YAP interaction, and promoted YAP nuclear translocation. Re-expression of EFNA3 partially reversed miR-210-3p-induced YAP activation and cytoprotection, confirming its functional involvement. Mechanistically, ischemia-induced HIF-1α increased miR-210-3p expression, which suppressed EFNA3 and facilitated YAP nuclear localization. EFNA3 re-expression partially reversed miR-210-3p-induced YAP activation, supporting its functional involvement. MiR-210-3p treatment was further associated with reduced oxidative injury, lipid peroxidation, mitochondrial dysfunction, and ferroptosis-related molecular alterations, together with improved perfusion and flap survival. In vivo, miR-210-3p improved local perfusion and flap survival. We further developed a virus-inspired biomimetic nanoparticle for miR-210-3p delivery, which achieved protective effects comparable to AAV-mediated delivery in vitro and in vivo. These findings identify the miR-210-3p-EFNA3-YAP axis as an important regulator of ischemic tissue adaptation and provide a non-viral miRNA delivery strategy for ischemic flap repair.
SN - 1477-3155
ER -