1,25(OH)2D3 Inhibited Ferroptosis in Zebrafish Liver Cells (ZFL) by Regulating Keap1-Nrf2-GPx4 and NF-κB-hepcidin Axis.

Ke Cheng,Yanqing Huang,Chunfang Wang

doi:10.3390/ijms222111334

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)2D3 on cell ferroptosis and its mechanism of action. The results showed that different incubation patterns of 1,25(OH)2D3 improved 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)2D3 preincubation for 72 h. Preincubation of ZFL at 200 pM 1,25(OH)2D3 for 72 h downgraded keap1 and ptgs2 gene expression, increased nrf2, ho-1, fth1, gpx4a,b expression, and lowered the expression of the nf-κb p65,il-6,il-1β gene, thus reducing the expression of hamp1. The above results indicate that different incubation patterns of 1,25(OH)2D3 have protective effects on ferroptosis of ZFL induced by ferroptosis activator RSL3 and 1,25(OH)2D3 can inhibit ferroptosis of ZFL by regulating Keap1–Nrf2–GPx4 and NF-κB–hepcidin axis.

Highlights

In recent years, in addition to the typical cell apoptosis, autophagy, pyroptosis, and necrosis, researchers found a new form of regulatory cell death—ferroptosis
Ferroptosis occurrence is related to the metabolism of iron, glutathione, reactive oxygen species (ROS), and lipid peroxidation (LPO)
Extracellular Fe3+ is transferred to the cell via transferrin and reduced to Fe2+, which reacts with excess H2 O2 in the cell to produce a large amount of ROS, promoting the production of intracellular LPO, and triggering ferroptosis [2]

Summary

Introduction

In addition to the typical cell apoptosis, autophagy, pyroptosis, and necrosis, researchers found a new form of regulatory cell death—ferroptosis. Ferroptosis was first discovered by Dixon et al [1] in the study of the death process of cancer cells. It refers to a form of regulatory cell death due to lethal lipid peroxidation. This new cell death mode is dependent on iron ions and is named ferroptosis. In terms of physiology and biochemistry, ferroptosis will lead to the increase in intracellular iron ion level, the generation of a large amount of ROS, the depletion of glutathione peroxidase 4

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