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Updated: Jun 23, 2026
Herbal Munziq Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting Inflammation
Published on: January 10, 2025
NUAK1 Inhibition Alleviates Ischemia-Reperfusion Injury via SYNE1-YAP1
Yangjinming Bai1, Tingting Zhao1, Qian Wang1
1Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China.
Background:
Mechanosensitive nuclear signaling contributes to myocardial ischemia-reperfusion injury, but the substrates and mechanisms of NUAK1 (AMPK-related kinase 5) remain unclear. We investigated whether NUAK1 regulates SYNE1 (Nesprin-1)/linker of nucleoskeleton and cytoskeleton-dependent nuclear gating of YAP1 (Yes-associated protein 1) during hypoxia/reoxygenation and ischemia-reperfusion injury.
Methods:
We integrated quantitative phosphoproteomics, biochemical assays, phosphosite-mutant analyses, subcellular fractionation, atomic force microscopy, and genetic or pharmacological NUAK1 inhibition in neonatal mouse ventricular myocytes and mouse models of ischemia-reperfusion injury to define the NUAK1-SYNE1-YAP1 axis.
Results:
Quantitative phosphoproteomics identified a conserved NUAK1-dependent phosphorylation site in Nesprin1-α2/SYNE1 (S434; S8284 in nesprin-1 giant), and biochemical assays supported direct SYNE1 phosphorylation by NUAK1. NUAK1 inhibition reduced apoptotic signaling and SYNE1 stability, enhanced YAP1 nuclear localization, and altered nuclear YAP1 dynamics. SYNE1 phosphosite-mutant and fractionation analyses indicated that NUAK1-SYNE1 restrains stress-induced YAP1 nuclear accumulation. Atomic force microscopy linked this pathway to nuclear mechanical remodeling. In mouse models of ischemia-reperfusion injury, NUAK1 inhibition reduced acute myocardial damage and improved remodeling indices.
Conclusions:
NUAK1-dependent SYNE1 phosphorylation shapes nuclear mechanosignaling during ischemic stress. NUAK1 downregulation promotes cardiomyocyte YAP1 nuclear activity and attenuates injury responses.
