Research progress of ceramides in the pathogenesis of diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Xue Sijia ,  Liu Kun

上海交通大學附屬上海市第一人民醫院眼科國家眼部疾病臨床醫學研究中心上海市眼底病重點實驗室上海眼視覺與光醫學工程技術研究中心上海市臨床重點專科, 上海 200080;

Corresponding?author：

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

Keywords：

Ceramide; Diabetic retinopathy; Sphingolipid metabolism; Review

DOI：

10.3760/cma.j.cn511434-202501024-00465

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 neuramide 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.

1.	Cheung N, Mitchell P, Wong TY. Diabetic retinopathy[J]. Lancet, 2010, 376(9735): 124-136. DOI: 10.1016/S0140-6736(09)62124-3.
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]. 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.
24.	Denis U, Lecomte M, Paget C, et al. Advanced glycation end-products induce apoptosis of bovine retinal pericytes in culture: involvement of diacylglycerol/ceramide production and oxidative stress induction[J]. Free Radic Biol Med, 2002, 33(2): 236-247. DOI: 10.1016/s0891-5849(02)00879-1.
25.	Choi RH, Tatum SM, Symons JD, et al. Ceramides and other sphingolipids as drivers of cardiovascular disease[J]. Nat Rev Cardiol, 2021, 18(10): 701-711. DOI: 10.1038/s41569-021-00536-1.
26.	Fort PE, Rajendiran TM, Soni T, et al. Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy[J/OL]. JCI insight, 2021, 6(19): e152109[2021-10-08]. https://pubmed.ncbi.nlm.nih.gov/34437304/. DOI: 10.1172/jci.insight.152109.
27.	Chen YY, Yang CM, Yang CH, et al. Elevated very-long-chain ceramides in the vitreous humor of patients with proliferative diabetic retinopathy[J/OL]. Invest Ophthalmol Vis Sci, 2025, 66(2): 28[2025-02-03]. https://pubmed.ncbi.nlm.nih.gov/39932474/. DOI: 10.1167/iovs.66.2.28.
28.	Filippov V, Song MA, Zhang K, et al. Increased ceramide in brains with Alzheimer's and other neurodegenerative diseases[J]. 2012, 29(3): 537-547. DOI: 10.3233/JAD-2011-111202.
29.	Lin G, Wang L, Marcogliese PC, et al. Sphingolipids in the pathogenesis of Parkinson's disease and parkinsonism[J]. Trends Endocrinol Metab, 2019, 30(2): 106-117. DOI: 10.1016/j.tem.2018.11.003.
30.	Li C, Wang L, Zhang J, et al. CERKL interacts with mitochondrial TRX2 and protects retinal cells from oxidative stress-induced apoptosis[J]. Biochim Biophys Acta, 2014, 1842(7): 1121-1129. DOI: 10.1016/j.bbadis.2014.04.009.
31.	García-Arroyo R, Domènech EB, Herrera-úbeda C, et al. Exacerbated response to oxidative stress in the retinitis pigmentosa cerkl^KD/KO mouse model triggers retinal degeneration pathways upon acute light stress[J/OL]. Redox biology, 2023, 66: 102862[2023-08-28]. https://pubmed.ncbi.nlm.nih.gov/37660443/. DOI: 10.1016/j.redox.2023.102862.
32.	Eade K, Gantner ML, Hostyk JA, et al. Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease[J]. Nat Metab, 2021, 3(3): 366-377. DOI: 10.1038/s42255-021-00361-3.
33.	Risner ML, Ribeiro M, McGrady NR, et al. Neutral sphingomyelinase inhibition promotes local and network degeneration in vitro and in vivo[J/OL]. Cell Commun Signal, 2023, 21(1): 305[2023-10-30]. https://pubmed.ncbi.nlm.nih.gov/37904133/. DOI: 10.1186/s12964-023-01291-1.
34.	Jiang XC, Paultre F, Pearson TA, et al. Plasma sphingomyelin level as a risk factor for coronary artery disease[J]. Arterioscler Thromb Vasc Biol, 2000, 20(12): 2614-2618. DOI: 10.1161/01.atv.20.12.2614.
35.	Haus JM, Kashyap SR, Kasumov T, et al. Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance[J]. Diabetes, 2009, 58(2): 337-343. DOI: 10.2337/db08-1228.
36.	Kropp M, De Clerck E, Vo TKS, et al. Short communication: unique metabolic signature of proliferative retinopathy in the tear fluid of diabetic patients with comorbidities-preliminary data for PPPM validation[J]. EPMA J, 2023, 14(1): 43-51. DOI: 10.1007/s13167-023-00318-4.
37.	Shen Y, Wang H, Fang J, et al. Novel insights into the mechanisms of hard exudate in diabetic retinopathy: findings of serum lipidomic and metabolomics profiling[J/OL]. Heliyon, 2023, 9(4): e15123[2023-03-31]. https://pubmed.ncbi.nlm.nih.gov/37089301/. DOI: 10.1016/j.heliyon.2023.e15123.
38.	Cremesti A, Paris F, Grassmé H, et al. Ceramide enables fas to cap and kill[J]. J Biol Chem, 2001, 276(26): 23954-23961. DOI: 10.1074/jbc.M101866200.
39.	Zhu D, Sreekumar PG, Hinton DR, et al. Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration[J]. Vision Res, 2010, 50(7): 643-651. DOI: 10.1016/j.visres.2009.09.002.
40.	Terao R, Honjo M, Ueta T, et al. Light stress-induced increase of sphingosine 1-phosphate in photoreceptors and its relevance to retinal degeneration[J/OL]. Int J Mol Sci, 2019, 20(15): 3670[2019-07-26]. https://pubmed.ncbi.nlm.nih.gov/31357484/. DOI: 10.3390/ijms20153670.
41.	Toops KA, Tan LX, Jiang Z, et al. Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium[J]. Mol Biol Cell, 2015, 26(1): 1-14. DOI: 10.1091/mbc.E14-05-1028.
42.	Tan LX, Germer CJ, La Cunza N, et al. Complement activation, lipid metabolism, and mitochondrial injury: converging pathways in age-related macular degeneration[J/OL]. Redox Biol, 2020, 37: 101781[2020-11-02]. https://pubmed.ncbi.nlm.nih.gov/33162377/. DOI: 10.1016/j.redox.2020.101781.
43.	Lewandowski D, Foik AT, Smidak R, et al. Inhibition of ceramide accumulation in AdipoR1-/- mice increases photoreceptor survival and improves vision[J/OL]. JCI insight, 2022, 7(4): e156301[2022-02-22]. https://pubmed.ncbi.nlm.nih.gov/35015730/. DOI: 10.1172/jci.insight.156301.
44.	Kannan R, Jin M, Gamulescu MA, et al. Ceramide-induced apoptosis: role of catalase and hepatocyte growth factor[J]. Free Radic Biol Med, 2004, 37(2): 166-175. DOI: 10.1016/j.freeradbiomed.2004.04.011.
45.	Hammerschmidt P, Ostkotte D, Nolte H, et al. CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity[J]. Cell, 2019, 177(6): 1536-1552. DOI: 10.1016/j.cell.2019.05.008.
46.	Tzou FY, Su TY, Lin WS, et al. Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress[J/OL]. Cell Rep, 2021, 35(2): 108972[2021-04-13]. https://pubmed.ncbi.nlm.nih.gov/33852856/. DOI: 10.1016/j.celrep.2021.108972.
47.	Mandal MN, Ambasudhan R, Wong PW, et al. Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression[J]. Genomics, 2004, 83(4): 626-635. DOI: 10.1016/j.ygeno.2003.09.020.
48.	Abcouwer SF, Lin CM, Wolpert EB, et al. Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury[J]. Invest Ophthalmol Vis Sci, 2010, 51(11): 5920-5933. DOI: 10.1167/iovs.10-5264.
49.	Kady NM, Liu X, Lydic TA, et al. ELOVL4-mediated production of very long-chain ceramides stabilizes tight junctions and prevents diabetes-induced retinal vascular permeability[J]. Diabetes, 2018, 67(4): 769-781. DOI: 10.2337/db17-1034.
50.	Yao X, Zhao Z, Zhang W, et al. Specialized retinal endothelial cells modulate blood-retina barrier in diabetic retinopathy[J]. Diabetes, 2024, 73(2): 225-236. DOI: 10.2337/db23-0368.
51.	Vandanmagsar B, Youm YH, Ravussin A, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance[J]. Nat Med, 2011, 17(2): 179-188. DOI: 10.1038/nm.2279.
52.	Elsherbini A, Bieberich E. Ceramide and exosomes: a novel target in cancer biology and therapy[J]. Adv Cancer Res, 2018, 140: 121-154. DOI: 10.1016/bs.acr.2018.05.004.
53.	Deng ZB, Zhuang X, Ju S, et al. Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells[J]. J Immunol, 2013, 190(7): 3579-3589. DOI: 10.4049/jimmunol.1203170.
54.	Opreanu M, Lydic TA, Reid GE, et al. Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid[J]. Invest Ophthalmol Vis Sci, 2010, 51(6): 3253-3263. DOI: 10.1167/iovs.09-4731.
55.	Alshaikh RA, Ryan KB, Waeber C. Sphingosine 1-phosphate, a potential target in neovascular retinal disease[J]. Br J Ophthalmol, 2022, 106(9): 1187-1195. DOI: 10.1136/bjophthalmol-2021-319115.
56.	Caballero S, Swaney J, Moreno K, et al. Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization[J]. Exp Eye Res, 2009, 88(3): 367-377. DOI: 10.1016/j.exer.2008.07.012.
57.	Yasuda S, Sumioka T, Iwanishi H, et al. Loss of sphingosine 1-phosphate receptor 3 gene function impairs injury-induced stromal angiogenesis in mouse cornea[J]. Lab Invest, 2021, 101(2): 245-257. DOI: 10.1038/s41374-020-00505-1.
58.	Eresch J, Stumpf M, Koch A, et al. Sphingosine kinase 2 modulates retinal neovascularization in the mouse model of oxygen-induced retinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(2): 653-661. DOI: 10.1167/iovs.17-22544.
59.	Kuo A, Checa A, Niaudet C, et al. Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis[J/OL]. Elife, 2022, 11: e78861[2022-10-05]. https://pubmed.ncbi.nlm.nih.gov/36197001/. DOI: 10.7554/eLife.78861.
60.	Terao R, Honjo M, Aihara M. Apolipoprotein M inhibits angiogenic and inflammatory response by sphingosine 1-phosphate on retinal pigment epithelium cells[J/OL]. Int J Mol Sci, 2017, 19(1): 112[2017-12-31]. https://pubmed.ncbi.nlm.nih.gov/29301231/. DOI: 10.3390/ijms19010112.
61.	Maines LW, French KJ, Wolpert EB, et al. Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases[J]. Invest Ophthalmol Vis Sci, 2006, 47(11): 5022-5031. DOI: 10.1167/iovs.05-1236.
62.	Sun Y, Fox T, Adhikary G, et al. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide[J]. J Leukoc Biol, 2008, 83(6): 1512-1521. DOI: 10.1189/jlb.0108076.
63.	álvarez-Barrios A, álvarez L, Sáenz de Santa María P, et al. Dysregulated lipid metabolism in a retinal pigment epithelial cell model and serum of patients with age-related macular degeneration[J/OL]. BMC Biol, 2025, 23(1): 96[2025-04-12]. https://pubmed.ncbi.nlm.nih.gov/40221802/. DOI: 10.1186/s12915-025-02198-8.
64.	Wang Q, Navitskaya S, Chakravarthy H, et al. Dual anti-inflammatory and anti-angiogenic action of miR-15a in diabetic retinopathy[J]. EBioMedicine, 2016, 11: 138-150. DOI: 10.1016/j.ebiom.2016.08.013.
65.	Fan L, Yan H. FTY720 attenuates retinal inflammation and protects blood-retinal barrier in diabetic rats[J]. Invest Ophthalmol Vis Sci, 2016, 57(3): 1254-1263. DOI: 10.1167/iovs.15-18658.
66.	Noda H, Takeuchi H, Mizuno T, et al. Fingolimod phosphate promotes the neuroprotective effects of microglia[J]. J Neuroimmunol, 2013, 256(1-2): 13-18. DOI: 10.1016/j.jneuroim.2012.12.005.
67.	Xie B, Shen J, Dong A, et al. Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization[J]. J Cell Physiol, 2009, 218(1): 192-198. DOI: 10.1002/jcp.21588.

1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy[J]. Lancet, 2010, 376(9735): 124-136. DOI: 10.1016/S0140-6736(09)62124-3.
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]. 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.
24. Denis U, Lecomte M, Paget C, et al. Advanced glycation end-products induce apoptosis of bovine retinal pericytes in culture: involvement of diacylglycerol/ceramide production and oxidative stress induction[J]. Free Radic Biol Med, 2002, 33(2): 236-247. DOI: 10.1016/s0891-5849(02)00879-1.
25. Choi RH, Tatum SM, Symons JD, et al. Ceramides and other sphingolipids as drivers of cardiovascular disease[J]. Nat Rev Cardiol, 2021, 18(10): 701-711. DOI: 10.1038/s41569-021-00536-1.
26. Fort PE, Rajendiran TM, Soni T, et al. Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy[J/OL]. JCI insight, 2021, 6(19): e152109[2021-10-08]. https://pubmed.ncbi.nlm.nih.gov/34437304/. DOI: 10.1172/jci.insight.152109.
27. Chen YY, Yang CM, Yang CH, et al. Elevated very-long-chain ceramides in the vitreous humor of patients with proliferative diabetic retinopathy[J/OL]. Invest Ophthalmol Vis Sci, 2025, 66(2): 28[2025-02-03]. https://pubmed.ncbi.nlm.nih.gov/39932474/. DOI: 10.1167/iovs.66.2.28.
28. Filippov V, Song MA, Zhang K, et al. Increased ceramide in brains with Alzheimer's and other neurodegenerative diseases[J]. 2012, 29(3): 537-547. DOI: 10.3233/JAD-2011-111202.
29. Lin G, Wang L, Marcogliese PC, et al. Sphingolipids in the pathogenesis of Parkinson's disease and parkinsonism[J]. Trends Endocrinol Metab, 2019, 30(2): 106-117. DOI: 10.1016/j.tem.2018.11.003.
30. Li C, Wang L, Zhang J, et al. CERKL interacts with mitochondrial TRX2 and protects retinal cells from oxidative stress-induced apoptosis[J]. Biochim Biophys Acta, 2014, 1842(7): 1121-1129. DOI: 10.1016/j.bbadis.2014.04.009.
31. García-Arroyo R, Domènech EB, Herrera-úbeda C, et al. Exacerbated response to oxidative stress in the retinitis pigmentosa cerkl^KD/KO mouse model triggers retinal degeneration pathways upon acute light stress[J/OL]. Redox biology, 2023, 66: 102862[2023-08-28]. https://pubmed.ncbi.nlm.nih.gov/37660443/. DOI: 10.1016/j.redox.2023.102862.
32. Eade K, Gantner ML, Hostyk JA, et al. Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease[J]. Nat Metab, 2021, 3(3): 366-377. DOI: 10.1038/s42255-021-00361-3.
33. Risner ML, Ribeiro M, McGrady NR, et al. Neutral sphingomyelinase inhibition promotes local and network degeneration in vitro and in vivo[J/OL]. Cell Commun Signal, 2023, 21(1): 305[2023-10-30]. https://pubmed.ncbi.nlm.nih.gov/37904133/. DOI: 10.1186/s12964-023-01291-1.
34. Jiang XC, Paultre F, Pearson TA, et al. Plasma sphingomyelin level as a risk factor for coronary artery disease[J]. Arterioscler Thromb Vasc Biol, 2000, 20(12): 2614-2618. DOI: 10.1161/01.atv.20.12.2614.
35. Haus JM, Kashyap SR, Kasumov T, et al. Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance[J]. Diabetes, 2009, 58(2): 337-343. DOI: 10.2337/db08-1228.
36. Kropp M, De Clerck E, Vo TKS, et al. Short communication: unique metabolic signature of proliferative retinopathy in the tear fluid of diabetic patients with comorbidities-preliminary data for PPPM validation[J]. EPMA J, 2023, 14(1): 43-51. DOI: 10.1007/s13167-023-00318-4.
37. Shen Y, Wang H, Fang J, et al. Novel insights into the mechanisms of hard exudate in diabetic retinopathy: findings of serum lipidomic and metabolomics profiling[J/OL]. Heliyon, 2023, 9(4): e15123[2023-03-31]. https://pubmed.ncbi.nlm.nih.gov/37089301/. DOI: 10.1016/j.heliyon.2023.e15123.
38. Cremesti A, Paris F, Grassmé H, et al. Ceramide enables fas to cap and kill[J]. J Biol Chem, 2001, 276(26): 23954-23961. DOI: 10.1074/jbc.M101866200.
39. Zhu D, Sreekumar PG, Hinton DR, et al. Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration[J]. Vision Res, 2010, 50(7): 643-651. DOI: 10.1016/j.visres.2009.09.002.
40. Terao R, Honjo M, Ueta T, et al. Light stress-induced increase of sphingosine 1-phosphate in photoreceptors and its relevance to retinal degeneration[J/OL]. Int J Mol Sci, 2019, 20(15): 3670[2019-07-26]. https://pubmed.ncbi.nlm.nih.gov/31357484/. DOI: 10.3390/ijms20153670.
41. Toops KA, Tan LX, Jiang Z, et al. Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium[J]. Mol Biol Cell, 2015, 26(1): 1-14. DOI: 10.1091/mbc.E14-05-1028.
42. Tan LX, Germer CJ, La Cunza N, et al. Complement activation, lipid metabolism, and mitochondrial injury: converging pathways in age-related macular degeneration[J/OL]. Redox Biol, 2020, 37: 101781[2020-11-02]. https://pubmed.ncbi.nlm.nih.gov/33162377/. DOI: 10.1016/j.redox.2020.101781.
43. Lewandowski D, Foik AT, Smidak R, et al. Inhibition of ceramide accumulation in AdipoR1-/- mice increases photoreceptor survival and improves vision[J/OL]. JCI insight, 2022, 7(4): e156301[2022-02-22]. https://pubmed.ncbi.nlm.nih.gov/35015730/. DOI: 10.1172/jci.insight.156301.
44. Kannan R, Jin M, Gamulescu MA, et al. Ceramide-induced apoptosis: role of catalase and hepatocyte growth factor[J]. Free Radic Biol Med, 2004, 37(2): 166-175. DOI: 10.1016/j.freeradbiomed.2004.04.011.
45. Hammerschmidt P, Ostkotte D, Nolte H, et al. CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity[J]. Cell, 2019, 177(6): 1536-1552. DOI: 10.1016/j.cell.2019.05.008.
46. Tzou FY, Su TY, Lin WS, et al. Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress[J/OL]. Cell Rep, 2021, 35(2): 108972[2021-04-13]. https://pubmed.ncbi.nlm.nih.gov/33852856/. DOI: 10.1016/j.celrep.2021.108972.
47. Mandal MN, Ambasudhan R, Wong PW, et al. Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression[J]. Genomics, 2004, 83(4): 626-635. DOI: 10.1016/j.ygeno.2003.09.020.
48. Abcouwer SF, Lin CM, Wolpert EB, et al. Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury[J]. Invest Ophthalmol Vis Sci, 2010, 51(11): 5920-5933. DOI: 10.1167/iovs.10-5264.
49. Kady NM, Liu X, Lydic TA, et al. ELOVL4-mediated production of very long-chain ceramides stabilizes tight junctions and prevents diabetes-induced retinal vascular permeability[J]. Diabetes, 2018, 67(4): 769-781. DOI: 10.2337/db17-1034.
50. Yao X, Zhao Z, Zhang W, et al. Specialized retinal endothelial cells modulate blood-retina barrier in diabetic retinopathy[J]. Diabetes, 2024, 73(2): 225-236. DOI: 10.2337/db23-0368.
51. Vandanmagsar B, Youm YH, Ravussin A, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance[J]. Nat Med, 2011, 17(2): 179-188. DOI: 10.1038/nm.2279.
52. Elsherbini A, Bieberich E. Ceramide and exosomes: a novel target in cancer biology and therapy[J]. Adv Cancer Res, 2018, 140: 121-154. DOI: 10.1016/bs.acr.2018.05.004.
53. Deng ZB, Zhuang X, Ju S, et al. Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells[J]. J Immunol, 2013, 190(7): 3579-3589. DOI: 10.4049/jimmunol.1203170.
54. Opreanu M, Lydic TA, Reid GE, et al. Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid[J]. Invest Ophthalmol Vis Sci, 2010, 51(6): 3253-3263. DOI: 10.1167/iovs.09-4731.
55. Alshaikh RA, Ryan KB, Waeber C. Sphingosine 1-phosphate, a potential target in neovascular retinal disease[J]. Br J Ophthalmol, 2022, 106(9): 1187-1195. DOI: 10.1136/bjophthalmol-2021-319115.
56. Caballero S, Swaney J, Moreno K, et al. Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization[J]. Exp Eye Res, 2009, 88(3): 367-377. DOI: 10.1016/j.exer.2008.07.012.
57. Yasuda S, Sumioka T, Iwanishi H, et al. Loss of sphingosine 1-phosphate receptor 3 gene function impairs injury-induced stromal angiogenesis in mouse cornea[J]. Lab Invest, 2021, 101(2): 245-257. DOI: 10.1038/s41374-020-00505-1.
58. Eresch J, Stumpf M, Koch A, et al. Sphingosine kinase 2 modulates retinal neovascularization in the mouse model of oxygen-induced retinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(2): 653-661. DOI: 10.1167/iovs.17-22544.
59. Kuo A, Checa A, Niaudet C, et al. Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis[J/OL]. Elife, 2022, 11: e78861[2022-10-05]. https://pubmed.ncbi.nlm.nih.gov/36197001/. DOI: 10.7554/eLife.78861.
60. Terao R, Honjo M, Aihara M. Apolipoprotein M inhibits angiogenic and inflammatory response by sphingosine 1-phosphate on retinal pigment epithelium cells[J/OL]. Int J Mol Sci, 2017, 19(1): 112[2017-12-31]. https://pubmed.ncbi.nlm.nih.gov/29301231/. DOI: 10.3390/ijms19010112.
61. Maines LW, French KJ, Wolpert EB, et al. Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases[J]. Invest Ophthalmol Vis Sci, 2006, 47(11): 5022-5031. DOI: 10.1167/iovs.05-1236.
62. Sun Y, Fox T, Adhikary G, et al. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide[J]. J Leukoc Biol, 2008, 83(6): 1512-1521. DOI: 10.1189/jlb.0108076.
63. álvarez-Barrios A, álvarez L, Sáenz de Santa María P, et al. Dysregulated lipid metabolism in a retinal pigment epithelial cell model and serum of patients with age-related macular degeneration[J/OL]. BMC Biol, 2025, 23(1): 96[2025-04-12]. https://pubmed.ncbi.nlm.nih.gov/40221802/. DOI: 10.1186/s12915-025-02198-8.
64. Wang Q, Navitskaya S, Chakravarthy H, et al. Dual anti-inflammatory and anti-angiogenic action of miR-15a in diabetic retinopathy[J]. EBioMedicine, 2016, 11: 138-150. DOI: 10.1016/j.ebiom.2016.08.013.
65. Fan L, Yan H. FTY720 attenuates retinal inflammation and protects blood-retinal barrier in diabetic rats[J]. Invest Ophthalmol Vis Sci, 2016, 57(3): 1254-1263. DOI: 10.1167/iovs.15-18658.
66. Noda H, Takeuchi H, Mizuno T, et al. Fingolimod phosphate promotes the neuroprotective effects of microglia[J]. J Neuroimmunol, 2013, 256(1-2): 13-18. DOI: 10.1016/j.jneuroim.2012.12.005.
67. Xie B, Shen J, Dong A, et al. Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization[J]. J Cell Physiol, 2009, 218(1): 192-198. DOI: 10.1002/jcp.21588.

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