Research progress on the role of ceramides in the pathogenesis and treatment of diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Xue Sijia ,  Liu Kun

Shanghai General Hospital, Shanghai Jiao Tong University School, National Eye Disease Clinical Medicine Research Center, Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai Engineering Research Center for Ophthalmology and Optic Medicine, Shanghai Key Clinical Specialties, Shanghai 200080, China;

Corresponding?author：

Liu Kun, Email: drliukun@sjtu.edu.cn

Keywords：

Ceramide; Diabetic retinopathy; Sphingolipid metabolism; Review

DOI：

10.3760/cma.j.cn511434-20251024-00465

Video：

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Abstract Full text Figures/Tables Video References Cited by

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes, seriously threatening the visual health of patients. Ceramide, as the core molecule of sphingolipid metabolism, abnormally accumulates in the retinal tissue of DR Patients and promotes the occurrence and development of DR By regulating pathological processes such as apoptosis, oxidative stress, inflammation and angiogenesis. Studies have shown that hyperglycemia can significantly alter the ceramide metabolic profile in the retina, leading to elevated levels and lipid toxicity. Moreover, there are regional changes in ceramide levels in the central area of the retina in DR Patients. Ceramides are involved in pathological processes such as retinal cell apoptosis, oxidative stress, mitochondrial dysfunction and blood-retinal barrier disruption, and shape the chronic inflammatory microenvironment of DR through pro-inflammatory and immunomodulatory effects. In addition, sphingosine 1-phosphate regulates vascular development through its receptor and has a bidirectional interaction with vascular endothelial growth factor, participating in the formation of retinal neovascularization. In terms of treatment strategies, the lipid omics characteristics of tears and serum are expected to be used for non-invasive monitoring of DR, while intervention measures targeting ceramide include the use of synthetic inhibitors, metabolic balance regulation drugs, antibody neutralization, and novel delivery systems, etc. Although the clinical transformation process of the ceramide pathway to DR is currently relatively lagging behind, in the future, it is necessary to move from "mechanism association" to "precise intervention", clarify its target specificity and elucidate its interaction with other pathways, in order to precisely enter the unmet clinical links such as metabolic disorders or neurodegeneration.

Citation： Xue Sijia, Liu Kun. Research progress on the role of ceramides in the pathogenesis and treatment of diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2026, 42(8): 731-738. doi: 10.3760/cma.j.cn511434-20251024-00465 Copy

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2. Tan TE, Wong TY. Diabetic retinopathy: looking forward to 2030[J/OL]. Front Endocrinol (Lausanne), 2023, 13: 1077669[2023-01-09]. https://pubmed.ncbi.nlm.nih.gov/36699020/. DOI: 10.3389/fendo.2022.1077669.
3. Lin KY, Hsih WH, Lin YB, et al. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy[J]. J Diabetes Investig, 2021, 12(8): 1322-1325. DOI: 10.1111/jdi.13480.
4. Shiwani HA, Elfaki MY, Memon D, et al. Updates on sphingolipids: spotlight on retinopathy[J/OL]. Biomed Pharmacother, 2021, 143: 112197[2021-09-21]. https://pubmed.ncbi.nlm.nih.gov/34560541/. DOI: 10.1016/j.biopha.2021.112197.
5. Dorweiler TF, Singh A, Ganju A, et al. Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy[J]. Cell Metab, 2024, 36(7): 1521-1533. DOI: 10.1016/j.cmet.2024.04.013.
6. Tippetts TS, Holland WL, Summers SA. Cholesterol-the devil you know; ceramide-the devil you don't[J]. Trends Pharmacol Sci, 2021, 42(12): 1082-1095. DOI: 10.1016/j.tips.2021.10.001.
7. Chaurasia B, Summers SA. Ceramides in metabolism: key lipotoxic players[J]. Annu Rev Physiol, 2021, 83: 303-330. DOI: 10.1146/annurev-physiol-031620-093815.
8. Di Pietro P, Izzo C, Abate AC, et al. The dark side of sphingolipids: searching for potential cardiovascular biomarkers[J/OL]. Biomolecules, 2023, 13(1): 168[2023-01-13]. https://pubmed.ncbi.nlm.nih.gov/36671552/. DOI: 10.3390/biom13010168.
9. Hannun YA, Obeid LM. Sphingolipids and their metabolism in physiology and disease[J]. Nat Rev Mol Cell Biol, 2018, 19(3): 175-191. DOI: 10.1038/nrm.2017.107.
10. Maceyka M, Sankala H, Hait NC, et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism[J]. J Biol Chem, 2005, 280(44): 37118-37129. DOI: 10.1074/jbc.M502207200.
11. Sinha T, Du J, Makia MS, et al. Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration[J/OL]. Proc Natl Acad Sci USA, 2021, 118(6): e2018956118[2021-02-09]. https://pubmed.ncbi.nlm.nih.gov/33526685/. DOI: 10.1073/pnas.2018956118.
12. Simón MV, Prado Spalm FH, Vera MS, et al. Sphingolipids as emerging mediators in retina degeneration[J/OL]. Front Cell Neurosci, 2019, 13: 246[2019-06-11]. https://pubmed.ncbi.nlm.nih.gov/31244608/. DOI: 10.3389/fncel.2019.00246.
13. Simon MV, Basu SK, Qaladize B, et al. Sphingolipids as critical players in retinal physiology and pathology[J/OL]. J Lipid Res, 2021, 62: 100037[2021-02-06]. https://pubmed.ncbi.nlm.nih.gov/32948663/. DOI: 10.1194/jlr.TR120000972.
14. Gómez-Mu?oz A, Waggoner DW, O'Brien L, et al. Interaction of ceramides, sphingosine, and sphingosine 1-phosphate in regulating DNA synthesis and phospholipase D activity[J]. J Biol Chem, 1995, 270(44): 26318-26325. DOI: 10.1074/jbc.270.44.26318.
15. Liu P, Anderson RG. Compartmentalized production of ceramide at the cell surface[J]. J Biol Chem, 1995, 270(45): 27179-27185. DOI: 10.1074/jbc.270.45.27179.
16. Opreanu M, Tikhonenko M, Bozack S, et al. The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models[J]. Diabetes, 2011, 60(9): 2370-2378. DOI: 10.2337/db10-0550.
17. Paris F, Grassmé H, Cremesti A, et al. Natural ceramide reverses Fas resistance of acid sphingomyelinase(-/-) hepatocytes[J]. J Biol Chem, 2001, 276(11): 8297-8305. DOI: 10.1074/jbc.M008732200.
18. Chalfant CE, Rathman K, Pinkerman RL, et al. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1[J]. J Biol Chem, 2002, 277(15): 12587-12595. DOI: 10.1074/jbc.M112010200.
19. Fox TE, Han X, Kelly S, et al. Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy[J]. Diabetes, 2006, 55(12): 3573-3580. DOI: 10.2337/db06-0539.
20. Alka K, Mohammad G, Kowluru RA. Regulation of serine palmitoyl-transferase and Rac1-Nox2 signaling in diabetic retinopathy[J/OL]. Sci Rep, 2022, 12(1): 16740[2022-10-06]. https://pubmed.ncbi.nlm.nih.gov/36202842/. DOI: 10.1038/s41598-022-20243-2.
21. Wei Y, Ji Y, Meng J, et al. Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis[J/OL]. Cardiovasc Diabetol, 2025, 24(1): 272[2025-07-10]. https://pubmed.ncbi.nlm.nih.gov/40640752/. DOI: 10.1186/s12933-025-02801-w.
22. Du YX, Zhao YT, Sun YX, et al. Acid sphingomyelinase mediates ferroptosis induced by high glucose via autophagic degradation of GPX4 in type 2 diabetic osteoporosis[J/OL]. Mol Med, 2023, 29(1): 125[2023-09-14]. https://pubmed.ncbi.nlm.nih.gov/37710183/. DOI: 10.1186/s10020-023-00724-4.
23. Chaurasia B, Tippetts TS, Mayoral Monibas R, et al. Targeting a ceramide double bond improves insulin resistance and hepatic steatosis[J]. Science, 2019, 365(6451): 386-392. DOI: 10.1126/science.aav3722.
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