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The causative genes,\n                    <jats:italic>WFS1<\/jats:italic>\n                    and\n                    <jats:italic>CISD2<\/jats:italic>\n                    , correspond to WS types 1 and 2, respectively. Here, we establish their mutual indispensability for inositol 1,4,5-triphosphate receptor (IP\n                    <jats:sub>3<\/jats:sub>\n                    R) activity, demonstrating their ability to restore reduced IP\n                    <jats:sub>3<\/jats:sub>\n                    R activity in WFS1- or CISD2-deficient mammalian cells. Additionally, our\n                    <jats:italic>Drosophila<\/jats:italic>\n                    WS models lacking\n                    <jats:italic>dWFS1<\/jats:italic>\n                    or\n                    <jats:italic>dCISD<\/jats:italic>\n                    exhibit diabetes-like phenotypes analogous to WS patients, and overexpression of\n                    <jats:italic>dWFS1<\/jats:italic>\n                    and\n                    <jats:italic>dCISD<\/jats:italic>\n                    in the flies alleviates their phenotypes. We have engineered a peptide containing the CDGSH domain of CISD2, critical for its interaction with IP\n                    <jats:sub>3<\/jats:sub>\n                    R. Overexpression of our CISD2 peptide or treatment with its cell-penetrating peptide (CPP)-conjugated form restores calcium homeostasis in WFS1- or CISD2-deficient cells, and overexpressing the homologous dCISD peptide suppresses diabetes-like phenotypes in WS model flies. These findings underscore the intricate involvements of WFS1 and CISD2 in ER calcium regulation and provide potential therapeutic prospects for WS-related diabetes.\n                  <\/jats:p>","DOI":"10.1038\/s44319-025-00436-2","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T18:39:29Z","timestamp":1743791969000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Reciprocal rescue of Wolfram syndrome by two causative genes"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5230-3386","authenticated-orcid":false,"given":"Su Jin","family":"Ham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3009-8144","authenticated-orcid":false,"given":"Eunju","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-9092","authenticated-orcid":false,"given":"Da Hyun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5737-210X","authenticated-orcid":false,"given":"Sehyeon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-1118","authenticated-orcid":false,"given":"Heesuk","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5894-7537","authenticated-orcid":false,"given":"Jongkyeong","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"436_CR1","doi-asserted-by":"crossref","first-page":"e145188","DOI":"10.1172\/jci.insight.145188","volume":"6","author":"D Abreu","year":"2021","unstructured":"Abreu D, Stone SI, Pearson TS, Bucelli RC, Simpson AN, Hurst S, Brown CM, Kries K, Onwumere C, Gu HJ et al (2021) A phase Ib\/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome. 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