Guanosine enhances thermogenesis and impairs KEAP1-mediated NRF2 degradation to resist ferroptosis in brown adipose tissue

Free Radic Biol Med. 2025 Jul 3:238:360-369. doi: 10.1016/j.freeradbiomed.2025.07.003. Online ahead of print.

Abstract

Brown adipose tissue (BAT) is the primary site of non-shivering thermogenesis, playing a crucial role in the regulation of glucose and lipid metabolism, as well as energy balance. In-depth research on BAT can aid in identifying therapeutic targets for various metabolic diseases. In this study, we conducted transcriptomic analysis and found significant changes in ferroptosis-related genes in BAT of mice following cold exposure. The notable decrease in GPX4 and reduced levels of glutathione, along with increased levels of malondialdehyde and ferrous ions, further suggest that ferroptosis may occur in mouse BAT under cold exposure. Cellular experiments indicated that the thermogenic and lipolytic capacities of brown adipocytes are impaired due to ferroptosis. Additionally, non-targeted metabolomic analysis revealed significant alterations in a group of purine nucleotide metabolites (GMP, guanosine, inosine, xanthine, hypoxanthine, and guanine) in mouse serum after cold exposure. Notably, guanosine was shown to enhance UCP1 expression and lipolytic capacity in brown adipocytes. Furthermore, guanosine can partially rescue ferroptosis of brown adipocytes by competitively binding to KEAP1, thereby activating the KEAP1-NRF2 pathway. Our study demonstrates that ferroptosis may occur in BAT under cold exposure, and guanosine acts as a thermogenic enhancer to resist cold-induced ferroptosis by targeting KEAP1 to disrupt KEAP1-NRF2 interaction.

Keywords: Brown adipose tissue; Ferroptosis; Guanosine; KEAP1-NRF2.