Ferroptosis, a recently discovered form of iron‐dependent cell death, requires an increased level of lipid‐reactive oxygen species (ROS). Ferritinophagy, a ferritin degradation pathway, depends on a selective autophagic cargo receptor (NCOA4). By screening various types of natural compounds, formosanin C (FC) was identified as a novel ferroptosis inducer, characterized by attenuations of FC‐induced viability inhibition and lipid ROS formation in the presence of ferroptosis inhibitor. FC also induced autophagic flux, evidenced by preventing autophagic marker LC3‐II degradation and increasing yellow LC3 puncta in tandem fluorescent‐tagged LC3 (mRFP‐GFP) reporter plasmid (ptfLC3) transfected cells when combined with autophagic flux inhibitor. It is noteworthy that FC‐induced ferroptosis and autophagic flux were stronger in HepG2 cells expressing higher NCOA4 and lower ferritin heavy chain 1 (FTH1) levels, agreeing with the results of gene expression analysis using CTRP and PRISM, indicating that FTH1 expression level exhibited a significant negative correlation with the sensitivity of the cells to a ferroptosis inducer. Confocal and electron microscopy confirmed the pronounced involvement of ferritinophagy in FC‐induced ferroptosis in the cells with elevated NCOA4. Since ferroptosis is a non‐apoptotic form of cell death, our data suggest FC has chemotherapeutic potential against apoptosis‐resistant HCC with a higher NCOA4 expression via ferritinophagy.
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