Targeting ER stress/ROS-driven VEGF signaling axis: AdipoRon as a multifunctional therapeutic agent for alkali burn-induced corneal neovascularization

  • Free Radic Biol Med. 2025 Sep 10:241:117-136. doi: 10.1016/j.freeradbiomed.2025.09.012.
Chunyang Wang  1 ,  Kelan Yuan  1 ,  Yaying Wu  1 ,  Tao Jiang  2 ,  Yujie Mou  1 ,  Ning Wang  1 ,  Xueping Chen  1 ,  Jiayun Yu  1 ,  Shuo Yang  3 ,  Xiuming Jin  4
Affiliations
  • 1. Zhejiang University, Eye Center of Second Affiliated Hospital, School of Medicine, China, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, 1 Xihu Avenue, Hangzhou, 310009, China.
  • 2. Department of Ophthalmology, Shaoxing Campus, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang, 312300, China; Department of Ophthalmology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China.
  • 3. Zhejiang University, Eye Center of Second Affiliated Hospital, School of Medicine, China, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, 1 Xihu Avenue, Hangzhou, 310009, China. Electronic address: [email protected].
  • 4. Zhejiang University, Eye Center of Second Affiliated Hospital, School of Medicine, China, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, 1 Xihu Avenue, Hangzhou, 310009, China. Electronic address: [email protected].
PMID: 40939851 DOI: 10.1016/j.freeradbiomed.2025.09.012
Abstract

Purpose: Corneal alkali burn-induced corneal neovascularization (CNV) can lead to blindness due to an increase in pro-inflammatory and pro-angiogenic factors following ocular surface damage. Although endoplasmic reticulum stress (ERS) and Adiponectin (ADPN) have been implicated in Other pathologies, their role in alkali-induced injury pathophysiology remains undefined. This study investigated the therapeutic mechanism of the ADPN receptor agonist, AdipoRon, in corneal alkali burns.

Methods: Firstly, the corneal alkali burn mice model was established and RNA Sequencing analyzed differential signaling pathways in injured corneas. Then, AdipoRon was administered via subconjunctival injection to observe its therapeutic effect and compare it to the ERS inhibitor 4-PBA. Assessments included ERS-related factors, oxidative stress (OS)-related factors, inflammatory cytokines, and vascular endothelial growth factor (VEGF) expression. Human umbilical vein endothelial cells (HUVECs) were used in vitro to explore the effect of AdipoRon on recombinant human VEGF (rhVEGF)-antagonized proliferation, migration and tube formation.

Results: AdipoRon significantly attenuated alkali burn-induced CNV, corneal opacity, and clinical injury severity, as well as neutrophil infiltration in mice by inhibiting ERS and VEGF expression. In addition, it concurrently reduced oxidative stress and inflammatory responses. In vitro, AdipoRon inhibited rhVEGF-induced HUVECs proliferation, migration and tube formation while downregulating VEGF expression.

Conclusions: These findings demonstrate that ERS critically regulates alkali burn-induced CNV and identify AdipoRon as a promising therapeutic agent for corneal alkali injury.

Keywords
AdipoRon; Alkali burn; Corneal limbus; Endoplasmic reticulum stress; Neovascularization; Oxidative stress.
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