Cordycepin Ameliorates Constant Light-Induced Thermogenic Dysfunction in Brown Adipose Tissue by Activating...

Constant light (LL) exposure is an established environmental risk factor for metabolic diseases, in which the whitening of brown adipose tissue (BAT) plays a critical role. This study aimed to elucidate the molecular mechanisms through which cordycepin counteracts LL-induced BAT whitening and improves metabolic function. We established an LL-exposed mouse model and employed an integrative approach combining pharmacological, metabolic, molecular, and computational (docking) assays to define cordycepin's effects and targets. Cordycepin treatment significantly improved cold tolerance and attenuated BAT whitening in LL mice. Mechanistically, cordycepin directly bound to and enhanced the activity of the NAD⁺-dependent deacetylase SIRT1. This activation mitigated LL-induced impairments in mitochondrial biogenesis, dynamics, and autophagy. Furthermore, SIRT1 activation rebalanced fatty acid metabolism by downregulating CD36 and upregulating CPT1, thereby restoring the coupling of fatty acid uptake to oxidation. All beneficial effects of cordycepin were abolished by the selective SIRT1 inhibitor EX-527. In summary, our work provides strong evidence that cordycepin directly interacts with SIRT1 and enhances its deacetylase activity, thereby restoring mitochondrial function and fatty acid oxidative homeostasis in BAT to counteract constant LL-induced metabolic dysfunction. These findings position cordycepin as a promising natural compound targeting the SIRT1 pathway for metabolic disorders.