ACLY Safeguards Copper Homeostasis to Sustain Brown Adipose Tissue Thermogenesis and Restrain Diet-Induced Obesity

Brown adipose tissue (BAT) plays a crucial role in maintaining energy balance and regulating glucose and lipid metabolism. Preserving BAT activity has been considered a potential strategy to mitigate metabolic dysfunctions such as diet-induced obesity (DIO). Here, we identified a pronounced copper overload in the BAT of DIO mice. Normalization of copper levels through copper chelation or cold exposure effectively restored the expression of the thermogenic effector protein UCP1, prevented BAT whitening, and improved systemic metabolic parameters. Proteomic profiling revealed ATP-citrate lyase (ACLY)-a key enzyme in acetyl-CoA synthesis and de novo lipogenesis-as a critical mediator in BAT copper homeostasis. ACLY expression was down-regulated in BAT of DIO mice but increased in cold-challenged or copper-chelated BAT. Loss of ACLY promoted NRF2 acetylation and nuclear translocation, leading to the transcriptional repression of the copper chaperone ATOX1, which exacerbated copper accumulation in BAT, resulting in BAT whitening and dysfunction. Connectivity Map screening identified succinylsulfathiazole (SST) as an upstream activator of ACLY expression. Both in vitro and in vivo administration of SST restored ACLY expression, corrected copper dysregulation, and re-established BAT activity. Collectively, these findings uncover a mechanism linking ACLY to copper homeostasis in BAT and highlight SST as a promising repurposed candidate for correcting obesity and BAT dysfunction-associated metabolic disorders.