EMBO Mol Med. 2025 Nov 26. doi: 10.1038/s44321-025-00335-y. Online ahead of print.
ABSTRACT
Obesity is a major global health challenge, and promoting the browning of white adipose tissue (WAT) represents a promising therapeutic strategy. However, pharmacological approaches to induce adipose thermogenesis remain limited. Through a Connectivity Map-based screen, we identified isomeranzin (ISM) as a potent small-molecule activator of WAT browning. ISM enhances thermogenesis in adipocytes by activating the AMP-activated protein kinase (AMPK) pathway. Integrated limited proteolysis-mass spectrometry, cellular thermal shift assays, and molecular docking identified guanine nucleotide-binding protein G(s) alpha subunit (Gnas) as the direct binding target of ISM. Mechanistic studies further revealed that ISM induces WAT browning through the Gnas-dependent activation of cAMP-AMPK signaling cascade. These findings elucidate the molecular mechanism underlying ISM activity and highlight its potential as a lead compound for enhancing energy expenditure and combating obesity.
PMID:41299101 | DOI:10.1038/s44321-025-00335-y