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Human retinal microvascular endothelial cells (HRMECs) were cultured in normal or high-glucose media, and\n                      <jats:italic>SLC7A11<\/jats:italic>\n                      expression modulated using small interfering RNA or lentiviral overexpression. Angiogenesis was assessed via proliferation, migration, and tube formation assays. Disulfidptosis was induced via acute glucose deprivation in high-glucose-adapted HRMECs and biochemically evaluated. A streptozotocin-induced diabetic mouse model was utilized to assess\n                      <jats:italic>SLC7A11<\/jats:italic>\n                      expression in vivo, and therapeutic efficacy was tested through weekly intravitreal lavage with glucose-free versus glucose-replete solutions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Disulfidptosis-related genes, particularly\n                      <jats:italic>SLC7A11<\/jats:italic>\n                      , were significantly upregulated in PDR FVMs, predominantly localizing to the vascular endothelium. In vitro, high-glucose conditions induced\n                      <jats:italic>SLC7A11<\/jats:italic>\n                      and vascular endothelial growth factor A expression in HRMECs, thereby promoting proliferation, migration, and tube formation.\n                      <jats:italic>SLC7A11<\/jats:italic>\n                      knockdown abrogated these pro-angiogenic effects, whereas overexpression exacerbated them. Critically, high-glucose-adapted cells developed a profound dependency on glucose; subsequent acute glucose deprivation triggered rapid cell death, exhibiting classic disulfidptosis features (F-actin collapse), a process that could not be rescued by ferroptosis inhibitors. In the diabetic mouse model,\n                      <jats:italic>SLC7A11<\/jats:italic>\n                      expression was similarly upregulated in the pathological retinal vasculature. Therapeutic vitreous lavage with a glucose-free solution significantly attenuated the progression of these pathological neovessels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results revealed a novel\n                      <jats:italic>SLC7A11<\/jats:italic>\n                      -mediated metabolic vulnerability in PDR. We demonstrated that exploiting this glucose dependency via localized deprivation induces disulfidptosis-like features in neovascular cells, representing a new therapeutic strategy for PDR.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40662-026-00511-2","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T02:08:04Z","timestamp":1791770884000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SLC7A11-mediated disulfidptosis underlies the pathogenesis of proliferative diabetic retinopathy"],"prefix":"10.1186","volume":"13","author":[{"given":"Bowei","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuilian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiutong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"511_CR1","doi-asserted-by":"publisher","first-page":"16012","DOI":"10.1038\/nrdp.2016.12","volume":"2","author":"TY Wong","year":"2016","unstructured":"Wong TY, Cheung CM, Larsen M, Sharma S, Sim\u00f3 R. 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All procedures involving animals complied with the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by the Animal Ethics and Experimentation Committee of the Affiliated Qingyuan Hospital (No. LAEC-202410-005). The protocol for using human patient samples was approved by the Ethical Committee of the Qingyuan Affiliated Hospital of Guangzhou Medical University (No. IRB-2024-194). All patients provided written informed consent before enrollment, and the specimens were managed according to the principles of the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"45"}}