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bioRxiv · 10.64898/2026.04.01.715734

Celastrol alleviates SGLT2 inhibitor-induced diabetic hyperketonemia by inhibiting hepatic ketogenesis

Zhu, Y.·Wang, Y.·Zhang, M.·Liu, L.·Tian, Y.·Guo, Z.·Zhang, R.·Zhang, J.·Ma, Z.·Fang, F.·Yan, L.·Liu, X.
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Abstract

SGLT2 inhibitor (SGLT2i)-induced diabetic hyperketonemia is a life-threatening acute complication of diabetes. While Celastrol has been reported to exert beneficial effects on obesity; its potential role in ketogenesis remains unclear. In this study, Celastrol administration significantly attenuates the fasting-induced elevation of blood {beta}-hydroxybutyrate. Moreover, a 7-day course of Celastrol (1 mg/kg/day) leads to reductions in body weight and fat mass. Mechanistically, Celastrol specifically downregulates HMGCS2 expression and suppressess hepatic ketogenesis through inhibiting PPAR expression in the short term ([≤] 2 days). However, after prolonged treatment for 7 days, Celastrol modulates both PPARand serum free fatty acids (FFAs) levels. Furthermore, anti-ketogenic effect of Celastrol is abolished in Ppar{square} /{square} mice. Importantly, Celastrol effectively ameliorates SGLT2i-induced hyperketonemia. In summary, Celastrol curbs hepatic ketone overproduction in a PPAR-dependent manner, indicating its protective potential against SGLT2i-induced hyperketonemia.

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Zhu, Y., Wang, Y., Zhang, M., Liu, L., Tian, Y., Guo, Z., Zhang, R., Zhang, J., Ma, Z., Fang, F., Yan, L., Liu, X.. 2026-04-05. Celastrol alleviates SGLT2 inhibitor-induced diabetic hyperketonemia by inhibiting hepatic ketogenesis. https://doi.org/10.64898/2026.04.01.715734

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