Dapagliflozin prevents methylglyoxal-induced retinal cell death in ARPE-19 cells

Trivedi, N, Quraishi, Z, Far, SKA, Ward, M, Conway, A, Abdulredha, R, Mshari, E and Shamsaldeen, YA ORCID: 0000-0001-8203-0067 (2026) Dapagliflozin prevents methylglyoxal-induced retinal cell death in ARPE-19 cells. FEBS Open Bio. ISSN 2211-5463

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Abstract

Diabetic macular oedema (DMO) is a sight-threatening complication of diabetes. Current research suggests methylglyoxal (MGO), an advanced glycation end product (AGE) and reactive oxygen species (ROS) precursor produced in states of chronic hyperglycaemia, may contribute to retinal damage in DMO. Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown antioxidant and anti-inflammatory properties in human brain neuronal cells. However, its protective effects in retinal cells remain unclear. This study investigates the potential protective role of current antidiabetics against MGO-induced cytotoxicity in human retinal pigment epithelial cells (ARPE-19), focussing on the NLRP3 and caspase-1 pathway. ARPE-19 cells were studied through four conditions: Control (untreated), MGO (1 nm and 1 mm), cotreatment of MGO (1 mm) with dapagliflozin (10 μm) to investigate cytotoxicity and cell viability through lactate dehydrogenase (LDH) and [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assays, respectively. Cells were further investigated using confocal microscopy to assess the presence and activation of NLRP3 and caspase-1 enzyme. MGO (1 mm) caused significant cytotoxicity by approximately 60%, which was reduced to 33% by dapagliflozin (10 μm), providing a significant level of protection to cells against MGO-induced cytotoxicity, in addition to a significant increase in cell viability from 60% to 83%, and reduction in NLRP3-independent caspase-1 activation and/or expression, associated with increased nuclear staining intensity reflecting potential nuclear condensation and pyroptosis. This study suggests dapagliflozin protects ARPE-19 cells from MGO-induced oxidative stress and inflammasome through reducing caspase-1 activation, underscoring its potential as a therapeutic approach for retinal inflammation and vascular dysfunction in DMO, which requires further clinical investigations.

Item Type:	Article
Uncontrolled Keywords:	SGLT2 inhibitors; dapagliflozin; diabetes; diabetic macular oedema; inflammasome; retinopathy; 3101 Biochemistry and cell biology; 3404 Medicinal and biomolecular chemistry
Subjects:	R Medicine > RE Ophthalmology R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	Wiley
Date of acceptance:	23 December 2025
Date of first compliant Open Access:	10 February 2026
Date Deposited:	10 Feb 2026 15:31
Last Modified:	10 Feb 2026 15:31
DOI or ID number:	10.1002/2211-5463.70191
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28090

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