<i>Mallotus japonicus</i> extract suppresses ferroptosis by inhibiting transferrin receptor-mediated ferrous ion uptake in human tubular epithelial HK2 cells

Iron (Fe) is the most abundant metal ion in the body, but its excess accumulation causes Fe²⁺-dependent and lipid peroxidation-dependent cell death (ferroptosis) via the production of reactive oxygen species (ROS). It is thought that ferroptosis is related to the progression of various kidney problems, including acute kidney injury and diabetic nephropathy. <i>Mallotus japonicus</i> (<i>M. japonicus</i>), a deciduous shrub belonging to the <i>Euphorbiaceae</i> family, contains ellagitannins such as corilagin, geraniin, mallotinic acid, and mallotusinic acid, which have antioxidant properties. Here, we investigated whether <i>M. japonicus</i> leaf extract inhibits ferroptosis in human proximal tubular epithelial HK2 cells. <i>M. japonicus</i> extract suppressed HK2 cell death caused by erastin, a ferroptosis inducer; this was accompanied by a reduction in intracellular Fe²⁺, ROS accumulation, and lipid peroxidation. Our findings suggested that the inhibitory effect of <i>M. japonicus</i> extract was due to the inhibition of transferrin receptor (CD71)-mediated Fe^3+/2+ uptake. Furthermore, we determined that mallotinic acid is a key compound that exhibits anti-ferroptosis effects. Overall, our results provide useful information for the use of <i>M. japonicus</i> extract in the treatment of kidney injuries.