{"doi":"10.3390/ijms241210276","title":"7-Ketocholesterol Promotes Retinal Pigment Epithelium Senescence and Fibrosis of Choroidal Neovascularization via IQGAP1 Phosphorylation-Dependent Signaling","abstract":"Accumulation of 7-ketocholesterol (7KC) occurs in age-related macular degeneration (AMD) and was found previously to promote fibrosis, an untreatable cause of vision loss, partly through induction of endothelial-mesenchymal transition. To address the hypothesis that 7KC causes mesenchymal transition of retinal pigment epithelial cells (RPE), we exposed human primary RPE (hRPE) to 7KC or a control. 7KC-treated hRPE did not manifest increased mesenchymal markers, but instead maintained RPE-specific proteins and exhibited signs of senescence with increased serine phosphorylation of histone H3, serine/threonine phosphorylation of mammalian target of rapamycin (p-mTOR), p16 and p21, β-galactosidase labeling, and reduced LaminB1, suggesting senescence. The cells also developed senescence-associated secretory phenotype (SASP) determined by increased IL-1β, IL-6, and VEGF through mTOR-mediated NF-κB signaling, and reduced barrier integrity that was restored by the mTOR inhibitor, rapamycin. 7KC-induced p21, VEGF, and IL-1β were inhibited by an inhibitor of protein kinase C. The kinase regulates IQGAP1 serine phosphorylation. Furthermore, after 7KC injection and laser-induced injury, mice with an IQGAP1 serine 1441-point mutation had significantly reduced fibrosis compared to littermate control mice. Our results provide evidence that age-related accumulation of 7KC in drusen mediates senescence and SASP in RPE, and IQGAP1 serine phosphorylation is important in causing fibrosis in AMD.","journal":"International Journal of Molecular Sciences","year":2023,"id":346270,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402269,"name":"Aniket Ramshekar","orcid":"0000-0002-0599-4337","position":1,"is_corresponding":false},{"id":963735,"name":"Thaonhi Cung","orcid":null,"position":2,"is_corresponding":false},{"id":928669,"name":"Chris Wallace‐Carrete","orcid":"0000-0002-4349-6283","position":3,"is_corresponding":false},{"id":1087146,"name":"Chandler J. Zaugg","orcid":null,"position":4,"is_corresponding":false},{"id":1086652,"name":"Jasmine Nguyen","orcid":"0000-0003-3227-2919","position":5,"is_corresponding":false},{"id":377012,"name":"Gregory J. Stoddard","orcid":"0000-0002-6292-276X","position":6,"is_corresponding":false},{"id":104133,"name":"M. Elizabeth Hartnett","orcid":"0000-0002-7270-5670","position":7,"is_corresponding":false},{"id":533477,"name":"Haibo Wang","orcid":"0000-0001-9976-5764","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:11:48.317335Z","pmid":"37373423","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}