Abstract

Ferroptosis is a kind of iron-dependent programed cell death. Vitamin D has been shown to be an antioxidant and a regulator of iron metabolism, but the relationship between vitamin D and ferroptosis is poorly studied in fish. This study used zebrafish liver cells (ZFL) to establish a ferroptosis model to explore the effect of 1,25(OH)2D3on cell ferroptosis and its mechanism of action. The results showed that different incubation patterns of 1,25(OH)2D3improved the survival rate of ZFL, mitigated mitochondrial damage, enhanced total glutathione peroxidase (GPx) activity, and reduced intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), and malondialdehyde (MDA), as well as iron ion levels, with the best effect at 200 pM 1,25(OH)2D3preincubation for 72 h. Preincubation of ZFL at 200 pM 1,25(OH)2D3for 72 h downgradedkeap1andptgs2gene expression, increasednrf2, ho-1, fth1, gpx4a,bexpression, and lowered the expression of thenf-κb p65,il-6,il-1βgene, thus reducing the expression ofhamp1.The above results indicate that different incubation patterns of 1,25(OH)2D3have protective effects on ferroptosis of ZFL induced by ferroptosis activator RSL3 and 1,25(OH)2D3can inhibit ferroptosis of ZFL by regulating Keap1–Nrf2–GPx4 and NF-κB–hepcidin axis.Keywords:ferroptosis;1,25(OH)2D3;zebrafish liver cells;Keap1–Nrf2–GPx4;NF-κB–hepcidin