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DDIT4 knockdown suppresses venous malformation progression by inhibiting NF-κB signaling as a potential therapeutic target

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机构: [1]Department of Oral and Marillofacial Surgery, The Pirst People's Hospital of Yunnan Province, Kunming. Yunnan 650032, China [2]The Afliated Hospital of Kunming University of Science and Technology, Kurming, Yurnan 650032, China [3]Yunnan Key Laboratory of Stomatology, Kurming Medical Untiversity, Kurming Yunnan 650500, China [4]The Afiliated Stomatology Hospital of Kunming Medical University, Kunming Yunnan 650031, China [5]The 920th Hospital of the Joint Lgistic Support Force of the Chinese People 's Liberation Arny, Kunning. Yunnan 650100, China [6]Shlyan Key Laboratory of Corrprehensive Prevention and Treatment of Oral Cancer, Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shlyan, Hubei 442000, China [7]Istiute of Oral Diseases, School of Denisty, Hubei University of Medicine, Shiyan, Hubei 42000, China [8]Kunming Stomatological Hospital North City District Branch, 650231, China
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关键词: Venous malformations DDIT4 NF-kB pathway Angiogenesis

摘要:
This study aims to investigate the regulatory role and underlying molecular mechanisms of DNA Damage Inducible Transcript 4 (DDIT4) in the pathogenesis of Venous Malformations (VMs), providing foundational experimental evidence for potential targeted therapies.Bioinformatic analysis identified DDIT4 as a key differentially expressed gene in VMs, and the sgGSEA method was employed to predict its potential biological functions. Immunohistochemical staining and immunofluorescence were performed to validate the expression level of DDIT4 and its association with vascular density. A lentiviral VMs cell model was established to assess DDIT4 expression levels. The effects of DDIT4 knockdown on VMs cell function were evaluated, with mechanistic insights gained through transcriptome sequencing and Western blot analysis. Further validation was performed using 3D VMs cell models and nude mouse xenografts with DDIT4 knockdown. Additionally, exogenous functional rescue experiments were conducted by activating the NF-κB pathway with lipopolysaccharide (LPS) in DDIT4 knockdown VMs 3D cell models and nude mouse xenografts to further investigate the role of DDIT4.DDIT4 was upregulated in VMs tissues and correlated with angiogenesis. DDIT4 knockdown increased cell roundness, inhibited proliferation, migration, and NF-κB pathway activation, and blocked angiogenesis in VMs 3D models and lesion formation in nude mouse xenografts, while suppressing the NF-κB pathway in both. NF-κB pathway activation restored angiogenesis in both models.DDIT4 knockdown inhibits VMs progression by suppressing the NF-κB pathway, suggesting that DDIT4 may serve as a potential therapeutic target.Copyright © 2025. Published by Elsevier Inc.

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大类 | 3 区 医学
小类 | 3 区 外周血管病
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第一作者机构: [3]Yunnan Key Laboratory of Stomatology, Kurming Medical Untiversity, Kurming Yunnan 650500, China [4]The Afiliated Stomatology Hospital of Kunming Medical University, Kunming Yunnan 650031, China [6]Shlyan Key Laboratory of Corrprehensive Prevention and Treatment of Oral Cancer, Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shlyan, Hubei 442000, China [7]Istiute of Oral Diseases, School of Denisty, Hubei University of Medicine, Shiyan, Hubei 42000, China
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通讯机构: [1]Department of Oral and Marillofacial Surgery, The Pirst People's Hospital of Yunnan Province, Kunming. Yunnan 650032, China [2]The Afliated Hospital of Kunming University of Science and Technology, Kurming, Yurnan 650032, China
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