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In a patient-derived IR D707A mouse model of severe insulin resistance, RF-409\u2014but not insulin\u2014activates the mutant receptor, restoring glucose regulation and ameliorating hyperglycemia, hyperinsulinemia, lipoatrophy, and pancreatic atrophy. Mechanistically, RF-409 engages the IR through a noncanonical binding geometry while stabilizing an active conformation resembling that induced by insulin. Phosphoproteomic profiling shows that RF-409 elicits broadly insulin-like signaling with distinct temporal features in receptor-proximal regulation. Together, these findings establish a framework for reactivating dysfunctional receptors and suggest broader applications beyond rare receptoropathies, including diabetes and liver disease.<\/jats:p>","DOI":"10.64898\/2026.05.04.722722","type":"posted-content","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T03:40:22Z","timestamp":1778211622000},"source":"Crossref","is-referenced-by-count":0,"title":["Reprogramming insulin receptor activation with a de novo agonist to overcome severe insulin resistance"],"prefix":"10.64898","author":[{"given":"Albert","family":"Hung","sequence":"first","affiliation":[{"name":"Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinru","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, WA, USA"},{"name":"Institute for Protein Design, 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