Ferroptosis Inhibitory Aromatic Abietane Diterpenoids from Ajuga decumbens and Structural Revision of Two 3,4-Epoxy Group-Containing Abietanes

Two new 3,4-epoxy group-containing abietane Diterpenoids (1 and 2), together with five known Diterpenoids (3-7), were isolated from Ajuga decumbens. Their structures were elucidated by spectroscopic data analysis, NMR calculations, and X-ray diffraction experiments. The structures of two known abietane Diterpenoids were revised based on NMR calculations and X-ray diffraction data. Notably, compound 4 specifically inhibited RSL3-induced Ferroptosis with an EC₅₀ of 56 nM by antioxidation. Moreover, 4 significantly decreased RSL3-induced lipid and cytosolic ROS accumulation and Ferroptosis marker gene PTGS2 mRNA expression. This work reports the most potent natural inhibitor against Ferroptosis found so far.