NMR-Guided Discovery of Luvunga D: A Novel Propellane-Type Limonoid from Luvunga scandens That Functions as a Non-Classical Ferroptosis Inhibitor

Recent phytochemical investigations have demonstrated that <i>Luvunga scandens</i> is a rich source of structurally diverse secondary metabolites; however, its potential antioxidant-active constituents and their underlying mechanisms remain largely unexplored. In this study, an NMR-guided fractionation strategy applied to the rhizomes and leaves of <i>L. scandens</i> led to the isolation of ten limonoids, including three new compounds, Luvungas B-D (<b>3</b>, <b>4</b>, and <b>8</b>). Their structures and absolute configurations were determined through extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Based on the isolated analogues, a biosynthetic pathway is proposed, featuring the metabolic bifurcation of a key acyclic intermediate into the isoobacunoic acid and propellane-type lineages. Biological evaluation revealed that <b>8</b> inhibits RSL3-induced ferroptosis in HepaRG liver cells with an EC₅₀ of 16.1 µM. Mechanistic studies demonstrated that, unlike classical antioxidants, compound <b>8</b> mitigates lipid peroxidation without exhibiting direct radical-scavenging or iron-chelating activities. These findings suggest that <b>8</b> suppresses ferroptosis via non-canonical mechanisms.