{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:36:59Z","timestamp":1776955019540,"version":"3.51.4"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["HL094505"],"award-info":[{"award-number":["HL094505"]}]},{"name":"National Institutes of Health","award":["HL169427"],"award-info":[{"award-number":["HL169427"]}]},{"name":"Judith Graham Pool Postdoctoral Fellowship from the National Bleeding Disorders Foundation","award":["HL094505"],"award-info":[{"award-number":["HL094505"]}]},{"name":"Judith Graham Pool Postdoctoral Fellowship from the National Bleeding Disorders Foundation","award":["HL169427"],"award-info":[{"award-number":["HL169427"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Missense mutations are the most prevalent alterations in genetic disorders such as hemophilia A (HA), which results from coagulation factor VIII (FVIII) deficiencies. These mutations disrupt protein biosynthesis, folding, secretion, and function. Current treatments for HA are extremely expensive and inconvenient for patients. Small molecule drugs offer a promising alternative or adjunctive strategy due to their lower cost and ease of administration, enhancing accessibility and patient compliance. By screening drug\/chemical libraries with cells stably expressing FVIII\u2013Gaussia luciferase fusion proteins, we identified compounds that enhance FVIII secretion and activity. Among these, suberoylanilide hydroxamic acid (SAHA) improved the secretion and activity of wild-type FVIII and common HA-associated missense mutants, especially mild and moderate ones. SAHA increased FVIII interaction with the endoplasmic reticulum chaperone BiP\/GRP78 but not with calreticulin. Lowering cellular BiP levels decreased SAHA-induced FVIII secretion and enhancing BiP expression increased FVIII secretion. SAHA also enhanced secretion and BiP interactions with individual domains of FVIII. In vivo, treating mice with SAHA or a BiP activator boosted endogenous FVIII activity. These findings suggest that SAHA serves as a proteostasis regulator, providing a novel therapeutic approach to improve the secretion and functionality of FVIII missense mutants prone to misfolding.<\/jats:p>","DOI":"10.3390\/biom15040458","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T07:25:00Z","timestamp":1742541900000},"page":"458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cell-Based Small-Molecule Screening Identifying Proteostasis Regulators Enhancing Factor VIII Missense Mutant Secretion"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9240-2047","authenticated-orcid":false,"given":"Vishal","family":"Srivastava","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6762-1095","authenticated-orcid":false,"given":"Zhigang","family":"Liu","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James C.","family":"Paton","sequence":"additional","affiliation":[{"name":"Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrienne W.","family":"Paton","sequence":"additional","affiliation":[{"name":"Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingwei","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7786-7580","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA"},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-021-00278-x","article-title":"Haemophilia","volume":"7","author":"Berntorp","year":"2021","journal-title":"Nat. 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