ArticleCirculation research2026
NUAK1 Inhibition Alleviates Ischemia-Reperfusion Injury via SYNE1-YAP1.
Article in Circulation research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMechanosensitive 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.
methodsWe 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.
resultsQuantitative 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.
conclusionsNUAK1-dependent SYNE1 phosphorylation shapes nuclear mechanosignaling during ischemic stress. NUAK1 downregulation promotes cardiomyocyte YAP1 nuclear activity and attenuates injury responses.
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