{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T18:34:18Z","timestamp":1786732458212,"version":"build-2736575974"},"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Animal models have limited ability to predict human metabolically dysfunction-associated steatohepatitis (MASH), creating a major obstacle in drug development. To address this challenge, we introduce an integrated drug discovery approach that combines rational small-interfering RNA (siRNA) design and chemical modifications to improve stability, validated in a complex human 3D NAC-organoid MASH model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using this system, we created new GalNAc-conjugated siRNAs targeting the 17\u03b2-hydroxysteroid dehydrogenase 13 (HSD17B13). The lead candidates were evaluated for stability in human serum and liver microsomes, off-target risks, and efficacy in the 3D organoid model that mimics key disease features such as steatosis and fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our main candidate, si-R5-42, demonstrated greater stability in human serum and liver microsomes, as well as fewer off-target risks. Most importantly, in the 3D organoid model, si-R5-42 successfully reduced disease markers. Its ability to lower hepatic steatosis and fibrogenesis was comparable to that of the clinical-phase candidate ARO-HSD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This research provides a promising therapeutic candidate and a solid, human-relevant preclinical siRNA testing framework, reducing dependence on animal models.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0354751","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:56:45Z","timestamp":1786730205000},"page":"e0354751","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A chemically optimized, GalNAc-conjugated siRNA targeting HSD17B13 demonstrates efficacy in a human 3D organoid model of MASH, showcasing an alternative to animal testing"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2345-2308","authenticated-orcid":true,"given":"Qin","family":"Meng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2747-1860","authenticated-orcid":true,"given":"Yuxuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudeep","family":"Pushpakom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"pone.0354751.ref001","doi-asserted-by":"crossref","first-page":"116723","DOI":"10.1016\/j.ejmech.2024.116723","article-title":"Decreasing the burden of non-alcoholic fatty liver disease: from therapeutic targets to drug discovery opportunities","volume":"277","author":"R Amorim","year":"2024","journal-title":"Eur J Med Chem"},{"issue":"11","key":"pone.0354751.ref002","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/s41575-024-00955-8","article-title":"A roadmap for clinical trials in MASH-related compensated cirrhosis","volume":"21","author":"JM Peric\u00e0s","year":"2024","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"3","key":"pone.0354751.ref003","doi-asserted-by":"crossref","first-page":"197","DOI":"10.7570\/jomes23052","article-title":"Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): a state-of-the-art review","volume":"32","author":"W-K Chan","year":"2023","journal-title":"J Obes Metab Syndr"},{"issue":"14","key":"pone.0354751.ref004","article-title":"Targeting extracellular RNA mitigates hepatic lipotoxicity and liver injury in NASH. 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