{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T21:19:24Z","timestamp":1771449564750,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,16]]},"group-title":"Cell Biology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01DK141142"],"award-info":[{"award-number":["R01DK141142"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL165797"],"award-info":[{"award-number":["R01HL165797"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL141353"],"award-info":[{"award-number":["R01HL141353"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,16]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function,\n                  <jats:italic>EF-Hand Domain Family Member D1<\/jats:italic>\n                  (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -dependent actin crosslinker, stabilizes endoplasmic reticulum\u2013mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca\n                  <jats:sup>2+<\/jats:sup>\n                  release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-dependent stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.\n                <\/jats:p>","DOI":"10.64898\/2026.02.13.705622","type":"posted-content","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T15:25:14Z","timestamp":1771255514000},"source":"Crossref","is-referenced-by-count":0,"title":["Excessive Ca\n                  <sup>2+<\/sup>\n                  -dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6538-8611","authenticated-orcid":false,"given":"David R.","family":"Eberhardt","sequence":"first","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9415-9191","authenticated-orcid":false,"given":"Emma C.","family":"Rekate","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmin B.","family":"Masini","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah E.","family":"Duron","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Mollinedo","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9015-418X","authenticated-orcid":false,"given":"Adrian M.","family":"Velarde","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devorah","family":"Stucki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-0367","authenticated-orcid":false,"given":"Sandra H. 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