Cataracts are the leading cause of blindness worldwide, and the mechanism underlying cataract formation is linked to the oxidative damage and the apoptosis of lens epithelial cells. Retinoic acid Receptor‐related orphan receptor α (RORα), a transcription factor, prevents oxidative stress and cell apoptosis. RORα is decreased in the lens from patients with cataract, but it remains unclear whether decreases in RORα are attributed to cataract formation.
Results:
Here, rat models of selenite-induced cataracts were used for in vivo experiments. In vitro, human lens epithelial cells (SRA01-04) were treated with selenite. RORα was downregulated in the lens from rat models of selenite-induced cataracts. The RORα agonist SR1078 significantly mitigated the degree of lens opacity. SR1078 reduced oxidative stress, cell apoptosis, and mitochondrial dysfunction and promoted the peroxisome proliferative activated receptor gamma coactivator (PGC-1α) and the nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 pathways in the lens from rat models of selenite-induced cataracts and lens epithelial cells upon selenite stimulation. RORα overexpression showed a similar protective effect on lens epithelial cells in vitro. Nerve growth factor (NGF) expression was up-regulated by RORα overexpression. Although RORα overexpression prevented selenite-induced damage to lens epithelial cells, the damage recurred following NGF knockdown.
Conclusion:
RORα protects against selenite-induced oxidative stress and cellular apoptosis. In the context of cataractogenesis, NGF is newly identified as a transcriptional target of RORα, and its reduction is related to mitochondrial dysfunction in lens epithelial cells. Our study highlights the translational potential of RORα activation as a nonsurgical cataract intervention. Antioxid. Redox Signal. 44, 599–617.
AloeL. Rita Levi-Montalcini: The discovery of nerve growth factor and modern neurobiology. Trends Cell Biol, 2004; 14(7):395–399; doi: 10.1016/j.tcb.2004.05.011
2.
AtkinsGB, HuX, GuentherMG, et al.Coactivators for the orphan nuclear receptor RORalpha. Mol Endocrinol, 1999; 13(9):1550–1557; doi: 10.1210/mend.13.9.0343
3.
BabizhayevMA. Mitochondria induce oxidative stress, generation of reactive oxygen species and redox state unbalance of the eye lens leading to human cataract formation: Disruption of redox lens organization by phospholipid hydroperoxides as a common basis for cataract disease. Cell Biochem Funct, 2011; 29(3):183–206; doi: 10.1002/cbf.1737
4.
BeakJY, KangHS, HuangW, et al.The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating caveolin-3-mediated mitophagy. J Biol Chem, 2021; 297(6):101358; doi: 10.1016/j.jbc.2021.101358
5.
BeakJY, KangHS, HuangW, et al.The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure. Am J Physiol Heart Circ Physiol, 2019; 316(1):H186–H200; doi: 10.1152/ajpheart.00531.2018
6.
BennmannD, WeidemannW, ThateA, et al.Aberrant O-GlcNAcylation disrupts GNE enzyme activity in GNE myopathy. FEBS J, 2016; 283(12):2285–2294; doi: 10.1111/febs.13729
7.
Blanco-MezquitaT, Martinez-GarciaC, ProençaR, et al.Nerve growth factor promotes corneal epithelial migration by enhancing expression of matrix metalloprotease-9. Invest Ophthalmol Vis Sci, 2013; 54(6):3880–3890; doi: 10.1167/iovs.12-10816
8.
BloemendalH. The vertebrate eye lens. Science, 1977; 197(4299):127–138; doi: 10.1126/science.877544
9.
BrennanLA, KantorowM. Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations. Exp Eye Res, 2009; 88(2):195–203; doi: 10.1016/j.exer.2008.05.018
10.
BunceGE, HessJL. Biochemical changes associated with selenite-induced cataract in the rat. Exp Eye Res, 1981; 33(5):505–514; doi: 10.1016/s0014-4835(81)80125-x
CaoSL, LuoHY, GaoYC, et al.TFP5-mediated CDK5 activity inhibition improves diabetic nephropathy via NGF/Sirt1 regulating axis. Front Cell Dev Biol, 2022; 10:829067; doi: 10.3389/fcell.2022.829067
13.
ChenLW, HorngLY, WuCL, et al.Activating mitochondrial regulator PGC-1α expression by astrocytic NGF is a therapeutic strategy for Huntington’s disease. Neuropharmacology, 2012; 63(4):719–732; doi: 10.1016/j.neuropharm.2012.05.019
14.
ChenX, XuJ, ChenX, et al.Cataract: Advances in surgery and whether surgery remains the only treatment in future. Adv Ophthalmol Pract Res, 2021; 1(1):100008; doi: 10.1016/j.aopr.2021.100008
15.
DaiC, XiongJ, WangY, et al.Nerve growth factor confers neuroprotection against colistin-induced peripheral neurotoxicity. ACS Infect Dis, 2020; 6(6):1451–1459; doi: 10.1021/acsinfecdis.0c00107
16.
FujiwaraH, TakigawaY, SuzukiT, et al.Superoxide dismutase activity in cataractous lenses. Jpn J Ophthalmol, 1992; 36(3):273–280.
17.
GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study. Trends in prevalence of blindness and distance and near vision impairment over 30 years: An analysis for the global burden of disease study. Lancet Glob Health, 2021; 9(2):e130–e143; doi: 10.1016/s2214-109x(20)30425-3
18.
GhinelliE, AloeL, CortesM, et al.Nerve growth factor (NGF) and lenses: Effects of NGF in an in vitro rat model of cataract. Graefes Arch Clin Exp Ophthalmol, 2003; 241(10):845–851; doi: 10.1007/s00417-003-0733-6
19.
GuoWY, WuQM, ZengHF, et al.A sinomenine derivative alleviates bone destruction in collagen-induced arthritis mice by suppressing mitochondrial dysfunction and oxidative stress via the NRF2/HO-1/NQO1 signaling pathway. Pharmacol Res, 2025; 215:107686; doi: 10.1016/j.phrs.2025.107686
20.
HahYS, YooWS, SeoSW, et al.Reduced NGF level promotes epithelial-mesenchymal transition in human lens epithelial cells exposed to high dexamethasone concentrations. Curr Eye Res, 2020; 45(6):686–695; doi: 10.1080/02713683.2019.1695844
21.
HammesHP, FederoffHJ, BrownleeM. Nerve growth factor prevents both neuroretinal programmed cell death and capillary pathology in experimental diabetes. Mol Med, 1995; 1(5):527–534.
22.
HanYH, KimHJ, KimEJ, et al.RORα decreases oxidative stress through the induction of SOD2 and GPx1 expression and thereby protects against nonalcoholic steatohepatitis in mice. Antioxid Redox Signal, 2014; 21(15):2083–2094; doi: 10.1089/ars.2013.5655
23.
HanYH, KimHJ, NaH, et al.RORα induces KLF4-mediated M2 polarization in the liver macrophages that protect against nonalcoholic steatohepatitis. Cell Rep, 2017; 20(1):124–135; doi: 10.1016/j.celrep.2017.06.017
24.
HarrisJM, LauP, ChenSL, et al.Characterization of the retinoid orphan-related receptor-alpha coactivator binding interface: A structural basis for ligand-independent transcription. Mol Endocrinol, 2002; 16(5):998–1012; doi: 10.1210/mend.16.5.0837
25.
JettenAM, TakedaY, SlominskiA, et al.Retinoic acid-related orphan receptor γ (RORγ): connecting sterol metabolism to regulation of the immune system and autoimmune disease. Curr Opin Toxicol, 2018; 8:66–80; doi: 10.1016/j.cotox.2018.01.005
26.
JieJ, JihaoR, ZhengL, et al.Unraveling morphine tolerance: CCL2 induces spinal cord apoptosis via inhibition of Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis. Brain Behav Immun, 2025; 124:347–362; doi: 10.1016/j.bbi.2024.12.011
27.
JomovaK, RaptovaR, AlomarSY, et al.Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging. Arch Toxicol, 2023; 97(10):2499–2574; doi: 10.1007/s00204-023-03562-9
28.
KimHJ, LeeSH, JeongC, et al.RORα-GABP-TFAM axis alleviates myosteatosis with fatty atrophy through reinforcement of mitochondrial capacity. J Cachexia Sarcopenia Muscle, 2024; 15(2):615–630; doi: 10.1002/jcsm.13432
29.
KimJY, ParkJH, KangSS, et al.Topical nerve growth factor attenuates streptozotocin-induced diabetic cataracts via polyol pathway inhibition and Na(+)/K(+)-ATPase upregulation. Exp Eye Res, 2021; 202:108319; doi: 10.1016/j.exer.2020.108319
30.
KimK, BooK, YuYS, et al.RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network. Nat Commun, 2017; 8(1):162; doi: 10.1038/s41467-017-00215-1
31.
KulbayM, WuKY, NirwalGK, et al.Oxidative stress and cataract formation: Evaluating the efficacy of antioxidant therapies. Biomolecules, 2024; 14(9):1055; doi: 10.3390/biom14091055
32.
LambiaseA, AloeL, CentofantiM, et al.Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma. Proc Natl Acad Sci U S A, 2009; 106(32):13469–13474; doi: 10.1073/pnas.0906678106
33.
LambiaseA, BoniniS, ManniL, et al.Intraocular production and release of nerve growth factor after iridectomy. Invest Ophthalmol Vis Sci, 2002; 43(7):2334–2340.
34.
LambiaseA, CentofantiM, MiceraA, et al.Nerve growth factor (NGF) reduces and NGF antibody exacerbates retinal damage induced in rabbit by experimental ocular hypertension. Graefes Arch Clin Exp Ophthalmol, 1997; 235(12):780–785; doi: 10.1007/bf02332863
35.
LambiaseA, ManniL, BoniniS, et al.Nerve growth factor promotes corneal healing: Structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci, 2000; 41(5):1063–1069.
36.
LiJ, BuonfiglioF, ZengY, et al.Oxidative stress in cataract formation: Is there a treatment approach on the horizon? Antioxidants (Basel), 2024; 13(10):1249; doi: 10.3390/antiox13101249
37.
MacGarveyNC, SulimanHB, BartzRR, et al.Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis. Am J Respir Crit Care Med, 2012; 185(8):851–861; doi: 10.1164/rccm.201106-1152OC
38.
MaoW, XiongG, WuY, et al.RORα suppresses cancer-associated inflammation by repressing respiratory complex I-dependent ROS generation. Int J Mol Sci, 2021; 22(19):10665; doi: 10.3390/ijms221910665
39.
MartoranaF, GaglioD, BiancoMR, et al.Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling. Cell Death Dis, 2018; 9(3):391; doi: 10.1038/s41419-018-0429-9
40.
MatsuokaH, KatayamaM, OhishiA, et al.Orphan nuclear receptor RORα regulates enzymatic metabolism of cerebral 24S-hydroxycholesterol through CYP39A1 intronic response element activation. Int J Mol Sci, 2020; 21(9):3309; doi: 10.3390/ijms21093309
41.
MoreauKL, KingJA. Protein misfolding and aggregation in cataract disease and prospects for prevention. Trends Mol Med, 2012; 18(5):273–282; doi: 10.1016/j.molmed.2012.03.005
42.
Moreno-SmithM, MilazzoG, TaoL, et al.Restoration of the molecular clock is tumor suppressive in neuroblastoma. Nat Commun, 2021; 12(1):4006; doi: 10.1038/s41467-021-24196-4
43.
NakazawaY, AokiM, IshiwaS, et al.Oral intake of α-glucosyl-hesperidin ameliorates selenite-induced cataract formation. Mol Med Rep, 2020; 21(3):1258–1266; doi: 10.3892/mmr.2020.10941
44.
NiederhauserO, MangoldM, SchubenelR, et al.NGF ligand alters NGF signaling via p75(NTR) and trkA. J Neurosci Res, 2000; 61(3):263–272; doi: 10.1002/1097-4547(20000801)61:3<263::aid-jnr4>3.0.co;2-m
45.
PalsamyP, BidaseeKR, ShinoharaT. Selenite cataracts: Activation of endoplasmic reticulum stress and loss of Nrf2/Keap1-dependent stress protection. Biochim Biophys Acta, 2014; 1842(9):1794–1805; doi: 10.1016/j.bbadis.2014.06.028
46.
PeriyasamyP, ShinoharaT. Age-related cataracts: Role of unfolded protein response, Ca(2+) mobilization, epigenetic DNA modifications, and loss of Nrf2/Keap1 dependent cytoprotection. Prog Retin Eye Res, 2017; 60:1–19; doi: 10.1016/j.preteyeres.2017.08.003
47.
PfaffA, ChernatynskayaA, VineyardH, et al.Thiol antioxidants protect human lens epithelial (HLE B-3) cells against tert-butyl hydroperoxide-induced oxidative damage and cytotoxicity. Biochem Biophys Rep, 2022; 29:101213; doi: 10.1016/j.bbrep.2022.101213
48.
QuanY, DuY, WuC, et al.Connexin hemichannels regulate redox potential via metabolite exchange and protect lens against cellular oxidative damage. Redox Biol, 2021; 46:102102; doi: 10.1016/j.redox.2021.102102
49.
SchieberM, ChandelNS. ROS function in redox signaling and oxidative stress. Current Biology: CB, 2014; 24(10):R453–R462; doi: 10.1016/j.cub.2014.03.034
50.
ShearerTR, McCormackDW, DeSartDJ, et al.Histological evaluation of selenium induced cataracts. Exp Eye Res, 1980; 31(3):327–333; doi: 10.1016/s0014-4835(80)80041-8
51.
ShihanMH, BalasubramanianR, WangY, et al.CD24 is required for sustained transparency of the adult lens. Exp Eye Res, 2025; 255:110347; doi: 10.1016/j.exer.2025.110347
52.
ShuDY, ChaudharyS, ChoKS, et al.Role of oxidative stress in ocular diseases: A balancing act. Metabolites, 2023; 13(2):187; doi: 10.3390/metabo13020187
53.
SiesH. Oxidative stress: Concept and some practical aspects. Antioxidants (Basel), 2020; 9(9):852; doi: 10.3390/antiox9090852
54.
SoltLA, BurrisTP. Action of RORs and their ligands in (patho)physiology. Trends Endocrinol Metab, 2012; 23(12):619–627; doi: 10.1016/j.tem.2012.05.012
55.
SunY, LiuCH, SanGiovanniJP, et al.Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation. Proc Natl Acad Sci U S A, 2015; 112(33):10401–10406; doi: 10.1073/pnas.1504387112
56.
SunY, LiuCH, WangZ, et al.RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. Faseb J, 2017a;31(10):4492–4502; doi: 10.1096/fj.201700172R
57.
SunZ, HuW, YinS, et al.NGF protects against oxygen and glucose deprivation-induced oxidative stress and apoptosis by up-regulation of HO-1 through MEK/ERK pathway. Neurosci Lett, 2017b;641:8–14; doi: 10.1016/j.neulet.2017.01.046
58.
TanitoM. Reported evidence of vitamin E protection against cataract and glaucoma. Free Radic Biol Med, 2021; 177:100–119; doi: 10.1016/j.freeradbiomed.2021.10.027
59.
TianX, WeiJ. Sestrin 2 protects human lens epithelial cells from oxidative stress and apoptosis induced by hydrogen peroxide by regulating the mTOR/Nrf2 pathway. Int J Immunopathol Pharmacol, 2024; 38:3946320241234741; doi: 10.1177/03946320241234741
60.
TsaiCF, WuJY, HsuYW. Protective effects of Rosmarinic acid against selenite-induced cataract and oxidative damage in rats. Int J Med Sci, 2019; 16(5):729–740; doi: 10.7150/ijms.32222
61.
TsaiMS, LinYC, SunCK, et al.Up-regulation of nerve growth factor in cholestatic livers and its hepatoprotective role against oxidative stress. PLoS One, 2014; 9(11):e112113; doi: 10.1371/journal.pone.0112113
62.
WangYN, RuanDY, WangZX, et al.Targeting the cholesterol-RORα/γ axis inhibits colorectal cancer progression through degrading c-myc. Oncogene, 2022; 41(49):5266–5278; doi: 10.1038/s41388-022-02515-3
63.
YangT, LinX, LiH, et al.Acetyl-11-keto-beta boswellic acid (AKBA) protects lens epithelial cells against H(2)O(2)-induced oxidative injury and attenuates cataract progression by activating Keap1/Nrf2/HO-1 signaling. Front Pharmacol, 2022; 13:927871; doi: 10.3389/fphar.2022.927871
64.
YaoQ, ZhouY, YangY, et al.Activation of Sirtuin1 by lyceum barbarum polysaccharides in protection against diabetic cataract. J Ethnopharmacol, 2020; 261:113165; doi: 10.1016/j.jep.2020.113165
65.
YeT, FanY, ZengX, et al.Induction of M1 polarization in BV2 cells by propofol intervention promotes perioperative neurocognitive disorders through the NGF/CREB signaling pathway: An experimental research. Int J Surg, 2025; 111(3):2439–2452; doi: 10.1097/js9.0000000000002257
66.
ZhangR, WeiY, ZhangS, et al.Inhibitory effect of idelalisib on selenite-induced cataract in Sprague Dawley rat pups. Curr Eye Res, 2022; 47(3):365–371; doi: 10.1080/02713683.2021.1988984
67.
ZhangY, LuoXY, WuDH, et al.ROR nuclear receptors: Structures, related diseases, and drug discovery. Acta Pharmacol Sin, 2015; 36(1):71–87; doi: 10.1038/aps.2014.120
68.
ZhaoM, LiY, LuC, et al.PGC1α degradation suppresses mitochondrial biogenesis to confer radiation resistance in glioma. Cancer Res, 2023; 83(7):1094–1110; doi: 10.1158/0008-5472.Can-22-3083
69.
ZhaoWJ, YanYB. Increasing susceptibility to oxidative stress by cataract-causing crystallin mutations. Int J Biol Macromol, 2018; 108:665–673; doi: 10.1016/j.ijbiomac.2017.12.013
70.
ZhuX, GuoK, LuY. Selenium effectively inhibits 1,2-dihydroxynaphthalene-induced apoptosis in human lens epithelial cells through activation of PI3-K/Akt pathway. Mol Vis, 2011; 17:2019–2027.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
