Triterpenoids from Uncaria macrophylla as ferroptosis inhibitors

Seven undescribed triterpenoids were obtained from the ethanol extract of the dried stems of Uncaria macrophylla Wall. (Rubiaceae).All of the isolates were urs-28-oic acid or olean-28-oic acid skeletons, including three triterpenoids with rare 3β,23-(1R-4-hydroxy-butyl-1,1-dioxy) or 23-(2R-tetrahydrofuran-2-oxy) substituents. Five triterpenoids showed promising inhibitory activity against erastin-induced ferroptosis in PC12 cells, while 3β,6α,23-trihydroxy-olean-12-en-28-oic acid was the most significant inhibitor to resist ferroptosis by activating the Nrf2/SLC7A11/GPx4 axis with an EC50 value of 4.2 ± 0.7 μM.