Evidence map›Paper›PMID 40072537›Full record

ArticleDiabetologia2025

MAP4K4 aggravates microvascular anomalies in diabetic retinopathy in a YTHDF2-dependent manner.

Qian Yang, Pei-Wen Zhu, Yan-Jun Wen, Ran Zhang, Wen-Wen Chen, Xin Huang, Qing Chang

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Article in Diabetologia, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

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3citing papers in PubMed
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3 · Its place in the literature

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3 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

7 authors.

Qian YangDepartment of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China.
Pei-Wen ZhuDepartment of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China.
Yan-Jun WenDepartment of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China.
Ran ZhangDepartment of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China.
Wen-Wen ChenDepartment of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China. wwchen16@fudan.edu.cn.ORCID http://orcid.org/0000-0002-3518-4351
Xin HuangDepartment of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China. fd2017huangxin@163.com.ORCID http://orcid.org/0000-0001-7988-3202
Qing ChangDepartment of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China. qngchang@aliyun.com.ORCID http://orcid.org/0000-0003-3733-8980

Funding

National Natural Science Foundation of China 82070975National Natural Science Foundation of China 82171078Shanghai Municipal Hospital Development Center SHDC2020CR5014-003Shanghai Science and Technology Development Foundation 18411965100
6 · The paper itself

Abstract

aims/hypothesisSignalling pathways that regulate endothelial cell (EC) dysfunction, ischaemia and inflammation play a crucial role in retinal microangiopathy such as diabetic retinopathy. MAP4K4 is highly expressed in ECs. However, the involvement of MAP4K4 in retinal vasculopathy of diabetic retinopathy remains unclear.

methodsWe analysed publicly available single-cell RNA sequencing (scRNA-seq) data from fibrovascular membranes (FVMs) from eight individuals with proliferative diabetic retinopathy (PDR) and normal retinas from 11 individuals without diabetes. Using db/db mice and human primary retinal endothelial cells (HRMECs), we further investigated the effects of MAP4K4 on retinal microangiopathy and endothelial dysfunction to explore the underlying regulatory mechanisms.

resultsThe scRNA-seq analysis revealed that MAP4K4 was predominantly expressed in retinal ECs, with elevated expression in FVMs from individuals with PDR compared with normal retinas from individuals without diabetes. This finding was confirmed at the protein level, with MAP4K4 expression and activity being upregulated in both the FVMs of individuals with PDR and the retinas of db/db mice. Inhibition of MAP4K4 using DMX-5804 alleviated retinal microvascular leakage by enhancing the expression and integrity of junctional proteins in both ECs from db/db mice and HRMECs. Additionally, DMX-5804 reduced retinal angiogenesis by inhibiting EC migration and vascular sprouting. Mechanistically, MAP4K4 regulated EC characteristics through NF-κB signalling pathway activity. The exacerbating effect of recombinant MAP4K4 on diabetic retinopathy in db/db mice was mitigated by a p65 inhibitor, confirming the involvement of NF-κB. Moreover, MAP4K4 expression was regulated by YTH N CONCLUSIONS/

interpretationOur study highlights the critical role of MAP4K4 in EC dysfunction and diabetic retinal microangiopathy, providing new insights into its molecular pathogenesis. Targeting MAP4K4, particularly through modulation of the YTHDF2/MAP4K4/NF-κB axis, may provide a novel therapeutic strategy for diabetic retinopathy.

Indexed as

Diabetic RetinopathyIntracellular Signaling Peptides and ProteinsMicrovesselsProtein Serine-Threonine KinasesRNA-Binding ProteinsAnimalsEndothelial CellsFemaleHumansMaleMiceMice, Inbred C57BLRetinaRetinal VesselsSignal TransductionIntracellular Signaling Peptides and ProteinsMAP4K4 protein, humanProtein Serine-Threonine KinasesRNA-Binding ProteinsDiabetic retinopathyEndothelial cellIntercellular junctionMAP4K4YTHDF2

Identifiers

PMID40072537

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