Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Mar 15, 2025; 16(3): 92003
Published online Mar 15, 2025. doi: 10.4239/wjd.v16.i3.92003
LEF1 influences diabetic retinopathy and retinal pigment epithelial cell ferroptosis via the miR-495-3p/GRP78 axis through lnc-MGC
Yi-Yi Luo, Xue-Ying Ba, Ling Wang, Ye-Pin Zhang, Hong Xu, Pei-Qi Chen, Li-Bo Zhang, Jian Han, Heng Luo
Yi-Yi Luo, Xue-Ying Ba, Jian Han, Heng Luo, Precision Medicine Center of Chuxiong Yi Autonomous Prefecture, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
Ling Wang, Pei-Qi Chen, Department of Endocrinology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
Ye-Pin Zhang, Department of Pathology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
Hong Xu, Li-Bo Zhang, Heng Luo, Department of Ophthalmology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, Chuxiong 675000, Yunnan Province, China
Co-first authors: Yi-Yi Luo and Xue-Ying Ba.
Author contributions: Luo YY and Ba XY contributed equally to this work as co-first authors; Luo YY, Ba XY, Wang L, Zhang YP, Luo H were responsible for conceptualization, methodology, validation, formal analysis, investigation, data curation, writing-original draft, writing-review and editing; Xu H was responsible for project administration; Chen PQ was responsible for resources; Zhang LB and Han J were responsible for resources, software, formal analysis; all the authors have read and approved the final manuscript.
Supported by Science and Technology Program of Yunnan Provincial Department of Science and Technology-Basic Research Program, No. 202301BA070001-025.
Institutional review board statement: This study was reviewed and approved by the People's Hospital of Chuxiong Yi Autonomous Prefecture (2022-10).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the People's Hospital of Chuxiong Yi Autonomous Prefecture (2022-10).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Heng Luo, MD, Department of Ophthalmology, The People's Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of DaLi University, No. 318 Lucheng South Road, Chuxiong 675000, Yunnan Province, China. lh18987837533@163.com
Received: January 12, 2024
Revised: November 10, 2024
Accepted: December 11, 2024
Published online: March 15, 2025
Processing time: 375 Days and 6.6 Hours
Abstract
BACKGROUND

Diabetic retinopathy (DR) is one of the major eye diseases contributing to blindness worldwide. Endoplasmic reticulum (ER) stress in retinal cells is a key factor leading to retinal inflammation and vascular leakage in DR, but its mechanism is still unclear.

AIM

To investigate the potential mechanism of LEF1 and related RNAs in DR.

METHODS

ARPE-19 cells were exposed to high levels of glucose for 24 hours to simulate a diabetic environment. Intraperitoneally injected streptozotocin was used to induce the rat model of DR. The expression levels of genes and related proteins were measured by RT-qPCR and Western blotting; lnc-MGC and miR-495-3p were detected by fluorescent in situ hybridization; CCK-8 and TUNEL assays were used to detect cell viability and apoptosis; enzyme-linked immunosorbent assay was used to detect inflammatory factors; dual-luciferase gene assays were used to verify the targeting relationship; and the retina was observed by HE staining.

RESULTS

LEF1 and lnc-MGC have binding sites, and lnc-MGC can regulate the miR-495-3p/GRP78 molecular axis. In high glucose-treated cells, inflammation was aggravated, the intracellular reactive oxygen species concentration was increased, cell viability was reduced, apoptosis was increased, the ER response was intensified, and ferroptosis was increased. As an ER molecular chaperone, GRP78 regulates the ER and ferroptosis under the targeting of miR-495-3p, whereas inhibiting LEF1 can further downregulate the expression of lnc-MGC, increase the level of miR-495-3p, and sequentially regulate the level of GRP78 to alleviate the occurrence and development of DR. Animal experiments indicated that the knockdown of LEF1 can affect the lnc-MGC/miR-495-3p/GRP78 signaling axis to restrain the progression of DR.

CONCLUSION

LEF1 knockdown can regulate the miR-495-3p/GRP78 molecular axis through lnc-MGC, which affects ER stress and restrains the progression of DR and ferroptosis in retinal pigment epithelial cells.

Keywords: Diabetic retinopathy; Endoplasmic reticulum stress; miR-495-3p/GRP78; Lnc-MGC; Retinal pigment epithelium cells; Ferroptosis

Core Tip: Inhibiting lnc-MGC protects retinal pigment epithelium cells from high glucose-induced apoptosis, inflammation and oxidative stress. Lnc-MGC targeted miR-495-3p and miR-495-3p targeted GRP78. Lnc-MGC regulated endoplasmic reticulum stress and ferroptosis via miR-495-3p/GRP78. LEF1 regulated diabetic retinopathy as binding protein of lnc-MGC.