{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T15:28:26Z","timestamp":1770910106794,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,9]]},"group-title":"Pharmacology and Toxicology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL137799"],"award-info":[{"award-number":["HL137799"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL156856"],"award-info":[{"award-number":["HL156856"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["TPA97002"],"award-info":[{"award-number":["TPA97002"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,9]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>Obesity remains a major global health challenge with limited durable pharmacotherapies. Disulfiram (DSF), an FDA-approved drug reported to inhibit gasdermin D (GSDMD), has been proposed to improve metabolic outcomes through suppression of inflammasome signaling. Here, we demonstrate that GSDMD is dispensable for high-fat diet\u2013induced obesity and insulin resistance, as neither genetic deletion nor antisense-mediated inhibition of GSDMD confers metabolic protection. In contrast, DSF robustly protects against obesity and IR through a GSDMD-independent mechanism. These effects are not attributable to reduced caloric intake but instead reflect a coordinated reprogramming of systemic lipid handling. Under steady-state conditions, DSF suppresses basal lipid oxidation while promoting fecal fatty acid excretion. In striking contrast, during acute lipid challenge, DSF enhances tissue lipid utilization and accelerates systemic clearance. Together, these findings overturn the prevailing inflammasome-centric model and establish context-dependent regulation of lipid partitioning\u2014rather than inflammasome inhibition\u2014as the primary mechanism underlying DSF\u2019s anti-obesity effects<\/jats:p>","DOI":"10.64898\/2026.02.06.704424","type":"posted-content","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T02:40:18Z","timestamp":1770691218000},"source":"Crossref","is-referenced-by-count":0,"title":["Disulfiram Protects Against Diet-Induced Obesity by Reprogramming Systemic Lipid Partitioning Independent of GSDMD"],"prefix":"10.64898","author":[{"given":"Babunageswararao","family":"Kanuri","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohan R","family":"Varshney","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krishna P","family":"Maremanda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nitin","family":"Nitin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelina","family":"Akomea","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dipanjan","family":"Chattopadhyay","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve Ting-Yuan","family":"Yeh","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, 2855 Gazelle Ct, Carlsbad, CA 92010"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz Y","family":"Hanaoka","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C","family":"Rudolph","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA"},{"name":"Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0294-641X","authenticated-orcid":false,"given":"Prabhakara R.","family":"Nagareddy","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA"},{"name":"Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026021206351477000_2026.02.06.704424v1.1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1111\/obr.12551","article-title":"Obesity: a chronic relapsing progressive disease process. 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