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We hypothesised that regulatory miRNAs altered in the diabetic cornea, such as miR-10b-5p, may be responsible for these abnormalities. We aimed to understand the molecular impact of miR-10b-5p increase in human diabetic vs non-diabetic limbal epithelial cells (LECs) enriched in limbal epithelial stem cells by identifying its target genes and proteins and testing it as a potential therapy for inhibiting oxidative stress in diabetic corneas.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      LECs were isolated from diabetic and non-diabetic human autopsy corneas. Telomerase-immortalised human corneal epithelial cells (HCECs), primary LECs and ex vivo organ-cultured corneas were transfected with 50 nmol\/l hsa-miR-10b-5p mimic or miRNA inhibitor or siRNA against\n                      <jats:italic>GCLM<\/jats:italic>\n                      (glutamate-cysteine ligase modifier subunit) along with their respective controls using Lipofectamine RNAiMAX. Total RNA was extracted for transcriptomic analysis. Proteins were extracted, digested and quantified using LC-MS\/MS proteomics. Oxidative stress was induced using 200 \u00b5mol\/l hydrogen peroxide (H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      ) in transfected LECs and\/or HCECs post starvation. Cell lysates at 0, 3, 6, 9 and 24 h time points were analysed on western blots. Reactive oxygen species in transfected HCECs were measured using the DCFDA\/H2DCFDA\u2013Cellular ROS Assay Kit. Glutathione (GSH) levels were quantified using the GSH-Glo assay from H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      -treated LECs. Glutamate-cysteine ligase modifier subunit (GCLM) and lanthionine synthetase C-like protein 1 (LANCL1) protein expression levels were also analysed by immunostaining.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Integrative proteomic and genomic analysis of miR-10b- vs miRNA mimic control-transfected primary LECs identified\n                      <jats:italic>GCLM<\/jats:italic>\n                      and\n                      <jats:italic>LANCL1<\/jats:italic>\n                      as key miR-10b-5p targets (false discovery rate\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.05), validated by western blot and immunostaining. miR-10b- and siRNA-GCLM-transfected LECs 3 h after H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      treatment showed a significant reduction in glutathione\/glutathione disulfide (2GSH\/GSSG) ratio and overall GSH levels. Further, miR-10b-5p-transfected HCECs produced higher ROS levels, peaking at 12.67 \u00b1 0.22% at 6 h post H\u2082O\u2082 treatment, as compared with 10.41 \u00b1 0.20% in controls. This implicates downregulated LANCL1 in modulating cellular responses to oxidative damage. Both GCLM and LANCL1 were downregulated in ex vivo diabetic corneas, while inhibition of miR-10b-5p significantly restored their expression in diabetic organ-cultured corneas by immunostaining.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Our findings suggest that diabetes-overexpressed miR-10b disrupts redox balance by targeting\n                      <jats:italic>GCLM<\/jats:italic>\n                      and\n                      <jats:italic>LANCL1<\/jats:italic>\n                      , which potentially leads to increased oxidative stress and cellular vulnerability in diabetic corneas. Inhibiting miR-10b-5p restored antioxidant defences, suggesting a potential therapeutic strategy to mitigate oxidative stress and normalise corneal health in individuals with diabetes and preserve vision.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06558-5","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T21:27:33Z","timestamp":1760995653000},"page":"198-213","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Oxidative stress-regulatory role of miR-10b-5p in the diabetic human cornea revealed through integrated multi-omics analysis"],"prefix":"10.1007","volume":"69","author":[{"given":"Daxian","family":"Zha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Gamez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaghaiegh M.","family":"Ebrahimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagendra","family":"Verma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Poe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei A.","family":"Kramerov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onkar B.","family":"Sawant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chintda","family":"Santiskulvong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr B.","family":"Stotland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping P.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Van Eyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Ljubimov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4956-569X","authenticated-orcid":false,"given":"Mehrnoosh","family":"Saghizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,20]]},"reference":[{"key":"6558_CR1","doi-asserted-by":"publisher","first-page":"e130","DOI":"10.1016\/S2214-109X(20)30425-3","volume":"9","author":"R Bourne","year":"2021","unstructured":"Bourne R, Steinmetz JD, Flaxman S et al (2021) Trends in prevalence of blindness and distance and near vision impairment over 30 years: an analysis for the Global Burden of Disease Study. 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General research support was provided to Eversight by the Connecticut Lions Eye Research Foundation, the Lowell F. Johnson Foundation, the Eppley Foundation for Research, the William G. and Helen C. Hoffman Foundation and the Louise H. and David S. Ingalls Foundation. We would like to acknowledge the Cedars-Sinai Proteomics and Metabolomics Core facilities for the acquisition and analysis of proteomic data. We are grateful for the support of the Genomics Core facility at Cedars-Sinai Medical Center for performing RNA-seq analysis. This work was presented as a poster at the 2025 Cornea and Ocular Surface Biology, Pathology and Regeneration GRC, 16\u201321 February 2025, Ventura, CA.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"All results of this study are included in the manuscript and ESM. Data and resources are available upon request from the corresponding author. The RNA-seq dataset is available from the Gene Expression Omnibus (GEO) using the accession number GSE292721, and the proteomics data are available on MassIVE (ID: MSV000097328).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open access funding provided by SCELC, Statewide California Electronic Library Consortium. This work was supported by grants from the National Institutes of Health, R01 EY025377 (MS); R01EY029829 (MS); R01EY031377 (AVL); R01EY013431 (AVL); the California Institute for Regenerative Medicine (CIRM EDUC4-12751) (DZ); and funding from the Board of Governors Regenerative Medicine Institute (MS).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"DZ contributed to design and methodology, supervision, investigation and analyses, and writing, reviewing, editing and approving the manuscript. JG, SME, YW, NV, AJP and SW contributed to design and methodology, investigation and analysis, and reviewing, editing and approving the manuscript. RS, AAK, OBS, CS and ABS contributed to design and methodology, data collection and reviewing, editing and approving the manuscript. ZPW and JEVE contributed to conceptualisation, design and methodology, and reviewing, editing and approving the manuscript. AVL contributed to conceptualisation, design and methodology, supervision, funding acquisition, project administration, investigation and reviewing, editing and approving the manuscript. MS contributed to conceptualisation, design and methodology, supervision, investigation and analyses, funding acquisition, project administration and writing, reviewing, editing and approving the manuscript. MS is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}