Erythropoietin-derived peptide (HBSP) inhibits caspase-3/GSDME through HMGB1 to regulate pyroptosis and reduce diabetic retinopathy.

Authors

Zhiyong Zheng, Qing Liu, Xu Chen, Muzhen Huang, Qing Ye, Min Chen

Published in

Peptides. Pages 171520. Sep 23, 2026. Epub Sep 23, 2026.

Abstract

Pyroptosis exerts an important effect on the development of diabetic retinopathy (DR). Helix B surface peptide (HBSP) is derived from erythropoietin (EPO) and has a special role in diabetes. This study explored effect of HBSP on retinal pigment epithelium (RPE) cell pyroptosis in DR and its mechanism.
ARPE-19 cells were treated with high-glucose (HG) and HBSP. Mice were injected with streptozotocin (STZ) and treated with HBSP. HE staining analyzed pathological changes. EB staining tested integrity of blood-retinal barrier (BRB). RT-qPCR determined HMGB1 mRNA. Western blot detected HMGB1 and pyroptosis-related proteins (NLRP3, caspase-1, GSDMD, caspase-3, GSDME). CCK-8 determined viability of ARPE-19 cells. Changes of cell pyroptosis were observed by transmission electron microscopy.
In STZ-induced diabetic mice, retinal tissue exhibited typical DR lesion, BRB breakdown and increased pyroptosis-related proteins. HG reproduced these events in ARPE-19 cells: viability loss, ultrastructural pyroptotic morphology and activation of both canonical (caspase-1/GSDMD) and non-canonical (caspase-3/GSDME) pyroptotic pathways, with the latter being most pronounced. HBSP dose-dependently rescued retinal architecture, restored BRB integrity in vivo, and normalized HG-lowered cell viability in vitro. HBSP ameliorated HG-triggered pyroptosis, primarily by suppressing caspase-3/GSDME signaling pathway. HBSP alleviated HG-stimulated pyroptosis via downregulating HMGB1. HMGB1 knockdown alleviated HG-triggered pyroptosis, primarily by inhibiting caspase-3/GSDME signaling pathway. In vivo, overexpression of HMGB1 could reverse the therapeutic effect of HBSP and increase pyroptosis.
HBSP suppresses RPE cell pyroptosis by disrupting the HMGB1-caspase-3/GSDME axis, thereby mitigating DR. These findings could illuminate a promising therapeutic avenue for DR.

PMID:
42778023
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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