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To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor). In vivo, treatment of 8-month-old R345W\n                    <jats:sup>+\/+<\/jats:sup>\n                    knockin mice with CHIR (25 mg\/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is an important demonstration of small molecule\u2013based prevention of AMD-like pathology in ML\/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.178050","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T14:01:13Z","timestamp":1723039273000},"source":"Crossref","is-referenced-by-count":6,"title":["GSK3 inhibition reduces ECM production and prevents age-related macular degeneration\u2013like pathology"],"prefix":"10.1172","volume":"9","author":[{"given":"Sophia M.","family":"DiCesare","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio J.","family":"Ortega","sequence":"additional","affiliation":[{"name":"Department of 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