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Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>IFIH1<\/jats:italic>\n                      R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-\u03b1 secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from\n                      <jats:italic>IFIH1<\/jats:italic>\n                      R779H-mutated iPSC-derived DCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways.\n                      <jats:italic>IFIH1<\/jats:italic>\n                      R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-\u03b1 secretion. Among the DEGs,\n                      <jats:italic>PML<\/jats:italic>\n                      was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-\u03b1 secretion from\n                      <jats:italic>IFIH1<\/jats:italic>\n                      R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-\u03b1 secretion from\n                      <jats:italic>IFIH1<\/jats:italic>\n                      R779H-mutated DCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s10875-025-01933-8","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T08:07:36Z","timestamp":1759219656000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling"],"prefix":"10.1007","volume":"45","author":[{"given":"Bunki","family":"Natsumoto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Shoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motonori","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Otsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Taniguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiko","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keishi","family":"Fujio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"1933_CR1","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41577-021-00633-9","volume":"22","author":"YJ Crow","year":"2022","unstructured":"Crow YJ, Stetson DB. 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