Eudesmane Sesquiterpenoids from Dregea Volubilis Suppress Kidney Stones via Akt Signalling to Inhibit Oxalate Biosynthesis in Drosophila

Abstract Dregea volubilis has long been used in traditional medicine for the treatment of urolithiasis, yet its bioactive constituents and molecular mechanisms remain largely undefined. Here, molecular networking-guided UPLC-ESI-MS/MS analysis enabled the isolation of ten sesquiterpenoids, including eight previously undescribed compounds (compounds 1∼4, 6∼9). Among them, dregeaterpene A (1) exhibited potent anti-urolithic activity in Drosophila, surpassing the therapeutic efficacy of potassium citrate. Mechanistically, dregeaterpene A suppressed endogenous oxalate biosynthesis by restoring oxalate-impaired Akt phosphorylation, leading to the downregulation of Daao1 and Daao2, and the upregulation of Agxt. Consequently, oxalate accumulation and calcium oxalate stone formation were markedly reduced. Collectively, these findings identify eudesmane sesquiterpenoids from D. volubilis as bioactive anti-urolithic agents and establish Akt-dependent regulation of oxalate metabolism as their underlying mechanism of action, highlighting dregeaterpene A as a promising lead compound for the development of therapeutics against calcium oxalate urolithiasis.