Luo C, Zheng ZG, Zeng MQ, Xu H, Yu XM, Sun D, He DJ. Curcumol targets the FTO/MAFG-AS1 axis to alleviate diabetic retinopathy via epigenetic remodeling and nanodelivery-based microenvironment modulation. World J Diabetes 2025; 16(6): 107017 [DOI: 10.4239/wjd.v16.i6.107017]
Corresponding Author of This Article
Dong-Juan He, MD, Chief Physician, Deputy Director, Department of Endocrinology, The Second People’s Hospital of Quzhou, No. 338 Xin 'an Avenue, Qujiang District, Quzhou 324000, Zhejiang Province, China. hedongjuan1247@wmu.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Letter to the Editor
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Jun 15, 2025; 16(6): 107017 Published online Jun 15, 2025. doi: 10.4239/wjd.v16.i6.107017
Curcumol targets the FTO/MAFG-AS1 axis to alleviate diabetic retinopathy via epigenetic remodeling and nanodelivery-based microenvironment modulation
Cheng Luo, Zhi-Gang Zheng, Mei-Qi Zeng, Hui Xu, Xian-Mei Yu, Da Sun, Dong-Juan He
Cheng Luo, Department of Endocrinology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, Zhejiang Province, China
Zhi-Gang Zheng, Mei-Qi Zeng, Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, Zhejiang Province, China
Hui Xu, Department of Hospital Management, Quzhou Hospital of Traditional Chinese Medicine, Quzhou 324000, Zhejiang Province, China
Xian-Mei Yu, Dong-Juan He, Department of Endocrinology, The Second People’s Hospital of Quzhou, Quzhou 324000, Zhejiang Province, China
Da Sun, Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325000, Zhejiang Province, China
Co-first authors: Cheng Luo and Zhi-Gang Zheng.
Author contributions: Luo C and Zheng ZG conceptualization and writing the original draft; Zeng MQ and Xu H formal analysis and validation; Yu XM and Sun D conceptualization, writing, reviewing, and editing. All authors participated in drafting the manuscript and have read, contributed to, and approved the final version of the manuscript. Luo C and Zheng ZG reviewed and summarized the literature and wrote the first draft of the paper. Both authors made vital and integral contributions to completion of the project and therefore qualify as co-first authors of the paper. He DJ, as the corresponding author, played an important and integral role in the design of the study and preparation of the manuscript. He DJ supervised the study design, provided critical revisions, and ensured the integrity of the research findings. The collaboration between all authors was essential for the publication of this manuscript.
Supported by Quzhou Science and Technology Plan Project, No. 2024K076.
Conflict-of-interest statement: No author has stated that there are any commercial, professional, or personal conflicts of interest relevant to the study, proving that it complies with the principles of publishing ethics.
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: Dong-Juan He, MD, Chief Physician, Deputy Director, Department of Endocrinology, The Second People’s Hospital of Quzhou, No. 338 Xin 'an Avenue, Qujiang District, Quzhou 324000, Zhejiang Province, China. hedongjuan1247@wmu.edu.cn
Received: March 13, 2025 Revised: March 22, 2025 Accepted: April 2, 2025 Published online: June 15, 2025 Processing time: 92 Days and 20.6 Hours
Abstract
Diabetic retinopathy (DR) is a major microvascular complication of diabetes, with its pathogenesis involving metabolic memory, epigenetic dysregulation, and multi-cellular microenvironmental disorders. This study systematically investigates the mechanism by which curcumol ameliorates DR through regulation of the FTO/MAFG-AS1 epigenetic axis and reveals its therapeutic potential in targeting the retinal microenvironment via a nano-delivery system. Experimental results demonstrate that curcumol activates the demethylase activity of FTO, stabilizing the expression of the long non-coding RNA MAFG-AS1, thereby inhibiting high glucose-induced retinal endothelial cell inflammation, migration, and vascular leakage. Single-cell transcriptomic analysis further uncovered the dual role of FTO in DR: On the one hand, it promotes pathological angiogenesis in endothelial cells, while on the other hand, it exerts protective effects through MAFG-AS1-mediated antioxidative and anti-inflammatory functions. Moreover, this study proposes a multidimensional epigenetic regulatory network based on histone lactylation, N6-methyladenosine modification, and DNA methylation, and verifies that curcumol delays DR progression by coordinately modulating these modifications. To overcome the limitations of conventional therapies, this study innovatively designed a macrophage membrane-coated nano-delivery system, significantly enhancing the retinal targeting and bioavailability of curcumol. Finally, the study advocates a paradigm shift from passive treatment to early prevention, proposing a three-tiered intervention strategy that integrates epigenetic biomarkers with artificial intelligence-based risk assessment. These findings not only elucidate the multi-target regulatory mechanisms of curcumol but also provide a theoretical foundation for the development of precision therapies for DR based on epigenetic remodeling and microenvironmental synergistic intervention.
Core Tip: This study reveals curcumol's dual-action mechanism in diabetic retinopathy through FTO/MAFG-AS1 axis modulation and macrophage membrane-coated nanodelivery. Curcumol activates FTO demethylase to stabilize MAFG-AS1, suppressing hyperglycemia-induced vascular leakage and inflammation. Single-cell transcriptomics resolve FTO's paradoxical roles: Promoting pathological angiogenesis in endothelial cells while exerting antioxidant/anti-inflammatory effects via MAFG-AS1. A multidimensional epigenetic network integrates N6-methyladenosine, histone lactylation, and DNA methylation. Biomimetic nanoparticles enhance retinal targeting and bioavailability. The paradigm shifts from reactive treatment to artificial intelligence-guided prevention, emphasizing early intervention via metabolic memory disruption and multi-tiered clinical strategies. These findings advance precision therapy by synergizing epigenetics, nanotechnology, and systems biology.
