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

• Celastrol attenuates fasting-induced hyperketonemia and reduces body weight and fat mass in mice. • Celastrol suppresses hepatic ketogenesis by downregulating HMGCS2 expression via inhibition of PPARα. • The anti-ketogenic effect of celastrol is dependent on PPARα, as it is abolished in Pparα⁻/⁻ mice. • Celastrol effectively ameliorates SGLT2 inhibitor-induced hyperketonemia, suggesting a protective role against this complication.