ArticleScientific reports2026
PERK inhibition attenuates multi-program cell death through Nrf2/HO-1 activation in diabetic retinopathy with integrated proteomics and functional validation in HRECs.
Article in Scientific reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors.
Funding
Abstract
To investigate whether protein kinase R-like ER kinase (PERK) inhibition mitigates hyperglycemia (HG)-induced multi-modal cell death, including ferroptosis, apoptosis, and pyroptosis, in human retinal endothelial cells (RECs) (HRECs) through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, thereby providing a unified therapeutic strategy for diabetic retinopathy. HRECs were cultured in normal glucose (NG, 5.5 mM, 48 h) and HG (HG, 25 mM, 48 h) DMEM media, with or without the PERK inhibitor ISRIB or the ferroptosis inhibitor Fer-1. Protein expression profiles from NG and HG-treated cells were compared using tandem mass tag (TMT)-LC-MS/MS and subjected to bioinformatic analysis. Cell viability was assessed via CCK-8 assay. Ferroptosis markers (Malondialdehyde (MDA), reactive oxygen species (ROS), Fe2+, GSH, glutathione peroxidase 4 (GPX4)), apoptosis mediators (caspase-3, caspase-7, Bcl-2), and pyroptosis markers (NLRP3, caspase-1, gasdermin D (GSDMD)) were quantified through biochemical assays and ELISA. Expression levels of PERK, Nrf2, and HO-1 were analyzed by real-time quantitative PCR (RT-qPCR) and Western blotting. Proteomic analysis identified 247 differentially expressed proteins (DEPs) significantly enriched in ferroptosis and peroxisome proliferator-activated receptor (PPAR) signaling pathways. HG conditions induced concurrent ferroptosis (increased MDA, ROS, Fe2+; decreased ↓GSH, GPX4), apoptosis (elevated caspase-3 and caspase-7; reduced ↓Bcl-2), and pyroptosis (upregulated NLRP3, caspase-1, and GSDMD; all p < 0.001). Treatment with ISRIB reversed these effects by normalizing ferroptosis markers, suppressing apoptosis (reduced caspase-3 and caspase-7; increased ↑Bcl-2), and inhibiting pyroptosis (decreased ↓NLRP3, caspase-1, GSDMD). Mechanistically, ISRIB activated the Nrf2/HO-1 pathway while downregulating PERK, with no significant effects observed under normoglycemic conditions. PERK inhibition simultaneously attenuates HG-induced ferroptosis, apoptosis, and pyroptosis in HRECs via activation of the Nrf2/HO-1 pathway. This coordinated blockade presents a promising therapeutic strategy to preserve retinal vasculature in diabetic retinopathy.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.