Pharmacological inhibition of CLPP stabilizes LETMD1 to boost thermogenesis and alleviate obesity.

Obesity poses a severe global health burden, and activating adipose thermogenesis offers a promising therapeutic avenue. However, the contribution of mitochondrial proteostasis to thermogenic regulation remains elusive. Here, we identify mitochondrial protease CLPP as a negative regulator of adipose thermogenesis. Pharmacological suppression of CLPP activity enhances thermogenic programmes in adipocytes. Mechanistically, CLPP interacts with LETMD1 and promotes its degradation at the post-translational level, while LETMD1 stabilization is required for the thermogenic effects induced by CLPP suppression. In vivo, pharmacological suppression of CLPP activity using hinokiflavone significantly enhances energy expenditure, attenuates weight gain, and improves insulin sensitivity in obese mice. Collectively, our study identifies a CLPP-LETMD1 regulatory axis that regulates adipose thermogenesis and highlights CLPP suppression as a potential therapeutic strategy for obesity intervention.