MAP4K4 aggravates microvascular anomalies in diabetic retinopathy in a YTHDF2-dependent manner
Authors' conclusion
Our 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.
Study context
- Population
- Fibrovascular membranes (FVMs) from individuals with proliferative diabetic retinopathy (PDR) and normal retinas from individuals without diabetes; db/db mice and HRMECs
- Participants
- 8 vs 11
- Comparison
- PDR vs Normal retinas
- PDRn = 8
- Normal retinasn = 11reference
- Outcome
- Role of MAP4K4 in DR microangiopathy
Methodological detailsSingle-cell RNA sequencing (scRNA-seq) analysis of public data, db/db mice, human primary retinal endothelial cells
- scRNA-seq analysis of public data
- Db/db mice
- Human primary retinal endothelial cells
Main finding
As reported in the abstract
- MAP4K4 predominantly expressed in retinal endothelial cell (ECs), with elevated expression in FVMs from PDR vs normal retinas
- MAP4K4 expression and activity upregulated at protein level in PDR FVMs and db/db mouse retinas
- MAP4K4 inhibition with DMX-5804 alleviated retinal microvascular leakage by enhancing junctional protein expression and integrity
- DMX-5804 reduced retinal angiogenesis by inhibiting EC migration and vascular sprouting
- MAP4K4 regulated EC characteristics through NF-κB signalling; recombinant MAP4K4's exacerbation of DR in db/db mice mitigated by a p65 inhibitor
- MAP4K4 expression regulated by YTHDF2, which modulates MAP4K4 mRNA stability
Original publication
MAP4K4 aggravates microvascular anomalies in diabetic retinopathy in a YTHDF2-dependent manner. Diabetologia. Published 12 March 2025. doi:10.
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