Glaucocalyxin A

ISODON JAPONICUS VAR: glaucocalyx has demonstrated significant antitumor effects, although the underlying mechanisms remain unclear. Through the integration of network pharmacology and cellular metabolomics, this study investigated the mechanism by which its primary active component, glaucocalyxin A (GLA), inhibits non-small cell lung cancer (NSCLC). The research identified α-linolenic acid metabolism as a key pathway through which GLA exerts its therapeutic effects on NSCLC, and pinpointed critical targets, including PTGS2, PLA2G15, and EGFR. Molecular docking results revealed that GLA exhibits strong binding affinity to these core targets, suggesting a high potential for interaction. Molecular dynamics simulations further confirmed that the GLA complexes display favorable stability. These findings provide a theoretical foundation for elucidating the mechanisms of traditional Chinese medicine and its practical applications.

Glaucocalyxin A (GLA) is a bioactive diterpenoid isolated from Rabdosia japonica var. that has been applied for centuries in traditional Chinese medicine. Although GLA exhibits potent anticancer activity against various human cancer cells, its cellular targets remain largely unidentified. We reported here that GLA covalently modifies glutathione and selectively inhibits TrxR activity by primarily targeting the Sec498 residue of the protein. Pharmacologic inhibition of TrxR with GLA results in accumulation of reactive oxygen species, decreased total glutathione and thiols, collapse of the intracellular redox balance, and eventually induction of oxidative stress mediated apoptosis in triple-negative breast cancer cells. Importantly, knockdown of TrxR1 increases the sensitivity cells to GLA. Targeting TrxR by GLA thus discloses a newly identified molecular mechanism underlying the biological activity of GLA, and provides an in-depth insight in understanding the action of GLA in treatment of cancer.