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The absence of such cystic phenotypes in Pkhd1\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    mice underscores the need for novel models that better recapitulate the human disease. We developed kidney organoid\u2010on\u2010chip models that mimic patients\u2019 distal\u2010nephron cysts, identifying RAC1\/c\u2010FOS as potential therapeutic targets. However, critical questions remain regarding RAC1 activation during cyst formation, cyst origins, and underlying molecular mechanisms. Using a multifaceted approach, organoid\u2010on\u2010chip models, transgenic mice, and patient kidney samples, we identified reduced levels of SPTAN1, a cytoskeletal spectrin protein, as a key regulator of RAC1 activation and cystic pathology. SPTAN1\u2010mutant kidney organoids and mice exhibited distal\u2010nephron cysts, and elevated RAC1\/c\u2010FOS expression, consistent with ARPKD patients. Transcriptomics and live imaging revealed altered calcium signaling and increased intracellular calcium. Single\u2010cell RNA\u2010seq identified SLC8A1, a sodium\/calcium exchanger, as a marker distinguishing distal\/connecting tubules from collecting ducts in human kidneys, predominantly expressed in cystic epithelia in organoids and human ARPKD kidneys. Restoring SPTAN1 in PKHD1\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    organoids via CRISPR activation alleviated cystic phenotypes, normalized intracellular calcium, and reduced RAC1\/c\u2010FOS expression. These findings position SPTAN1 as a central player in ARPKD pathogenesis and highlight epigenome editing as a potential therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202524001","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T12:09:22Z","timestamp":1772971762000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Deciphering the Impact of RAC1\u2010SPTAN1 in ARPKD Cystogenesis Using Multifaceted Models"],"prefix":"10.1002","volume":"13","author":[{"given":"Shohei","family":"Kuraoka","sequence":"first","affiliation":[{"name":"Division of Nephrology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhei","family":"Higashi","sequence":"additional","affiliation":[{"name":"Division of Nephrology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suguru","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Cedars\u2010Sinai Medical Center  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solmaz","family":"Pourgonabadi","sequence":"additional","affiliation":[{"name":"Division of Nephrology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honami","family":"Honjoh","sequence":"additional","affiliation":[{"name":"Division of Nephrology Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Ishigaki","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Cedars\u2010Sinai Medical Center  Los Angeles California 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