SCARB2 is a key regulator in the progression of diabetic retinopathy, which modulates endothelial dysfunction by regulating the MAPK/ERK/MMP9 signaling pathway, identifying it as a novel potential therapeutic target.
Key Findings
Results
Transcriptome sequencing identified SCARB2 (Scavenger receptor class B member 2) as a potential core regulator of endothelial dysfunction in diabetic retinopathy.
Transcriptome sequencing was performed to screen for potential core regulators associated with endothelial dysfunction in DR.
SCARB2 was selected as a candidate from the transcriptomic screen for further validation.
Two experimental models were constructed for validation: a high-glucose (HG)-stimulated retinal microvascular endothelial cell model and a streptozotocin (STZ)-induced diabetic rat model.
Transcriptome sequencing confirmed SCARB2 as a potential core regulator of endothelial dysfunction in DR.
Results
SCARB2 expression is elevated under high-glucose conditions and exacerbates retinal microvascular endothelial cell injury.
Under high-glucose conditions, elevated SCARB2 was found to exacerbate retinal microvascular endothelial cell injury.
Western blot, tube formation assay, Transwell, EdU proliferation assay, immunofluorescence, and Evans Blue assay were conducted to evaluate the effect of SCARB2 on endothelial dysfunction.
SCARB2 is described as a lysosomal membrane protein, and lysosomal pathways play a key role in regulating endothelial injury in DR.
Results
Elevated SCARB2 promotes neovascularization and DR progression by upregulating VEGFR1 and VEGFA.
Elevated SCARB2 under high-glucose conditions promotes neovascularization and DR progression by upregulating VEGFR1 and VEGFA.
Tube formation assays were used to assess the role of SCARB2 in neovascularization.
The upregulation of angiogenic factors VEGFR1 and VEGFA was identified as a downstream consequence of elevated SCARB2.
Results
SCARB2 mediates endothelial cell migration and invasion through modulation of MMP9 via the MAPK/ERK pathway.
Mechanistically, SCARB2 modulates MMP9 via the MAPK/ERK pathway.
This signaling cascade mediates endothelial cell migration and invasion and facilitates pathological neovascularization.
RNA-seq analysis was used to explore the downstream signaling pathway of SCARB2.
Transwell assays were used to evaluate migration and invasion of retinal microvascular endothelial cells.
Results
SCARB2 regulation of endothelial dysfunction was validated in both in vitro high-glucose cell models and in vivo STZ-induced diabetic rat models.
A HG-stimulated retinal microvascular endothelial cell model served as the in vitro system.
A STZ-induced diabetic rat model served as the in vivo system.
Evans Blue assay was conducted in the animal model to evaluate vascular permeability, a hallmark of DR-associated endothelial dysfunction.
Immunofluorescence was used to assess protein localization and expression changes in both models.
Conclusions
SCARB2 is identified as a novel potential therapeutic target for the treatment of diabetic retinopathy.
The study concludes that SCARB2 is a key regulator in the progression of diabetic retinopathy.
SCARB2 modulates endothelial dysfunction by regulating the MAPK/ERK/MMP9 signaling pathway.
The authors state this study 'identifies SCARB2 as a novel potential therapeutic target for the treatment of diabetic retinopathy.'
Retinal microvascular endothelial cell dysfunction is described as central to DR pathogenesis, making SCARB2's role in this process therapeutically relevant.
What This Means
Diabetic retinopathy (DR) is the leading cause of preventable blindness among working-age adults and results from damage to the tiny blood vessels in the retina caused by high blood sugar. This research suggests that a protein found on the surface of lysosomes (the cell's recycling centers) called SCARB2 plays a central role in driving this damage. Using gene expression analysis, the researchers identified SCARB2 as a key player in the dysfunction of retinal blood vessel cells, and then confirmed its role using both cell cultures exposed to high glucose and diabetic rats.
This research suggests that when blood sugar is high, SCARB2 levels rise, which triggers a chain reaction inside retinal blood vessel cells: SCARB2 activates a signaling pathway (MAPK/ERK) that increases a protein called MMP9, which in turn promotes abnormal blood vessel growth (neovascularization) and cell migration—hallmarks of advanced diabetic retinopathy. Additionally, SCARB2 was found to boost levels of VEGFR1 and VEGFA, two well-known drivers of abnormal blood vessel formation in the eye.
This research matters because it identifies SCARB2 as a previously unrecognized regulator of diabetic retinopathy and maps out the specific molecular pathway it uses to cause harm. This could open the door to new treatments targeting SCARB2 or the MAPK/ERK/MMP9 pathway, potentially offering alternatives or complements to existing therapies for a condition that currently has limited treatment options once it reaches advanced stages.
Fan J, Cao W, Wang J, Hao Y, Zhang F, Tao Y, et al.. (2026). Lysosomal Membrane Protein SCARB2 Mediates the Pathogenesis of Diabetic Retinopathy Through the MAPK/ERK/MMP9 Signaling Pathway.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202601737R