Evidence map›Paper›PMID 41736035›Full record

ArticleJournal of translational medicine2026

A novel molecule ZYZ329 targeting histone methyltransferase SMYD3 suppresses pathological angiogenesis via the driven mitochondrial ROS/HIF-1α/VEGFA axis.

Qing Ye, Jianghong Cai, Xianneng Lu, Qi Zhu, Qixiu Li, Mi Ren, Qian Ding, Yicheng Mao, Yi Zhun Zhu

Abstract read
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In one paragraph

Article in Journal of translational medicine, 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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1 · What the graph read from it

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

9 authors.

Qing YeSchool of Pharmaceutical Sciences, Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, the Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, China.
Jianghong CaiLaboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau SAR, 999078, China.
Xianneng LuSchool of Pharmaceutical Sciences, Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, the Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, China.
Qi ZhuSchool of Pharmaceutical Sciences, Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, the Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, China.
Qixiu LiSchool of Pharmaceutical Sciences, Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, the Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, China.
Mi RenThe Cancer Center of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Qian DingLaboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau SAR, 999078, China.
Yicheng MaoSchool of Pharmaceutical Sciences, Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, the Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, China. maoyc@fudan.edu.cn.
Yi Zhun ZhuSchool of Pharmaceutical Sciences, Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, the Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, China. yzzhu@must.edu.mo.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundThe histone methyltransferase SMYD3 (SET and MYND domain containing 3) is critical for vascular homeostasis and may be implicated in pathological angiogenesis. However, its mechanism remains elusive, and targeted inhibitors are in early-stage development. We aim to clarify whether SMYD3 regulates angiogenesis and develop novel molecules targeting SMYD3.

methodsExpression profile of SMYD3 under pro-angiogenic conditions was characterized by bioinformatics analysis and endothelial cell (EC) validation. The effects of SMYD3 knockdown, knockdown-overexpression, and overexpression on angiogenesis were validated, including Matrigel neovascularization, aortic ring sprouting, and EC tube formation. Regarding molecule development, virtual screening, structural modifications, molecular docking, inhibition screening of EC proliferation, and SMYD3 enzyme activity and cellular thermal shift assays were employed. A novel molecule ZYZ329 was identified and evaluated in angiogenesis. Mechanistic studies involved genetic approaches and the mitochondrial reactive oxygen species (mROS) scavenger MitoQ (Mitoquinone mesylate). Finally, a murine hindlimb ischemia model and rat skin healing model were established to evaluate ZYZ329 on pathological and physiological angiogenesis.

resultsSMYD3 was upregulated in endothelial cells under ischemic, hypoxic, and VEGF-stimulated conditions. And SMYD3 gene knockdown, overexpression after knockdown, and overexpression regulated the angiogenesis capacity of endothelial cells. After virtual screening and structural modifications, the novel molecule ZYZ329 was developed for dual inhibition of EC proliferation (IC50 = 6.147 μM) and SMYD3 enzymatic function (IC50 = 0.419 μM). The ZYZ329 engaged SMYD3 in cells, and exhibited a certain degree of selectivity for SMYD3. Moreover, ZYZ329 significantly attenuated pathological angiogenesis in a dose-dependent manner. Mechanistically, genetic or pharmacological inhibition of SMYD3 impaired HIF-1α stabilization and downstream VEGFA production. SMYD3 genetic perturbation modulated mROS without affecting apoptosis in hypoxic endothelial cell. MitoQ intervention confirmed that moderate SMYD3-driven mROS elevation regulates the HIF-1α/VEGFA axis in angiogenesis. In hindlimb ischemia model, ZYZ329 significantly impaired blood flow recovery and post-ischemic angiogenesis, demonstrating superior efficacy to EPZ031686. However, ZYZ329 had no significant effect on physiological angiogenesis.

conclusionsSMYD3 drives angiogenesis partially via the mROS/HIF-1α/VEGFA axis. We developed a novel molecule ZYZ329, which potently suppresses pathological angiogenesis. This offers potential therapeutic target and lead structures for treating angiogenesis-related diseases.

Indexed as

Histone-Lysine N-MethyltransferaseHypoxia-Inducible Factor 1, alpha SubunitMitochondriaNeovascularization, PathologicReactive Oxygen SpeciesSignal TransductionVascular Endothelial Growth Factor AAnimalsCell ProliferationEndothelial CellsHindlimbHumansHuman Umbilical Vein Endothelial CellsIschemiaMaleMolecular Docking SimulationHistone-Lysine N-MethyltransferaseHypoxia-Inducible Factor 1, alpha SubunitReactive Oxygen SpeciesSMYD3 protein, humanVascular Endothelial Growth Factor AAngiogenesisEndothelial cellHIF-1αSMYD3ZYZ329

Identifiers

PMID41736035
PMCPMC13040898

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.