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bioRxiv · 10.64898/2026.07.20.739085

Dronedarone hydrochloride reverses obesity-related metabolic syndrome while preserving skeletal muscle mass

Lei, J.·Zhang, X.·cao, x.·zhu, z.·ye, f.·xu, z.·su, w.·zeng, x.·zhao, j.·jiang, s.·zhao, n.·Liu, H.·Lu, Y.·Sun, C.·Chai, J.
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Abstract

Obesity-driven metabolic syndrome poses a critical global threat, yet standard therapies like GLP-1 receptor agonists trigger substantial lean mass wasting, with muscle loss accounting for up to 40% of reduced weight. Here we identify a non-canonical metabolic application for dronedarone hydrochloride, an anti-arrhythmic benzofuran derivative. In diet-induced and ob/ob obese mice, short-term dronedarone hydrochloride administration dose-dependently reduces food intake, clears visceral and subcutaneous adiposity, and reverses steatohepatitis. Head-to-head trials show that dronedarone hydrochloride achieves glycemic control and fat clearance non-inferior to semaglutide, tirzepatide, and empagliflozin, but uniquely and completely preserves skeletal muscle mass. Mechanistically, dronedarone hydrochloride operates independently of central hypothalamic appetite-regulating neuropeptides and the peripheral leptin pathway. By decoupling fat reduction from sarcopenia, our findings establish dronedarone hydrochloride as a muscle-sparing therapeutic candidate for metabolic syndrome.

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Lei, J., Zhang, X., cao, x., zhu, z., ye, f., xu, z., su, w., zeng, x., zhao, j., jiang, s., zhao, n., Liu, H., Lu, Y., Sun, C., Chai, J.. 2026-07-23. Dronedarone hydrochloride reverses obesity-related metabolic syndrome while preserving skeletal muscle mass. https://doi.org/10.64898/2026.07.20.739085

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