1,3-Dichloro-2-propanol Induced Renal Cell Ferroptosis via the Circadian Clock Protein BMAL1 Targeting GPX4

Abstract

1,3-Dichloro-2-propanol (1,3-DCP), a representative chloropropyl alcohol contaminant in food, has shown toxic effects on the kidney. Ferroptosis is a newly identified cell death driven by iron-dependent lipid peroxidation that is associated with renal injury. However, the role of 1,3-DCP in ferroptosis in renal cells remains unclear. In this study, we found that ferroptosis was involved in a 1,3-DCP-induced renal injury. Mechanistically, we revealed that 1,3-DCP triggered ferroptosis by inhibiting GPX4 activity and disturbing iron homeostasis in NRK-52E cells. The circadian clock is crucial in modulating physiological cellular functions through the regulation of various downstream proteins. Furthermore, our findings also showed that 1,3-DCP triggered ferroptosis through interference with the circadian clock. The data showed that the expression of GPX4 was regulated by clock core protein BMAL1. 1,3-DCP interfered with GPX4 rhythmic expression through disordering BMAL1 and led to lipid peroxidation, ultimately inducing ferroptosis. In conclusion, our study uncovered that BMAL1 was responsible for controlling GPX4 to mediate 1,3-DCP-induced ferroptosis. The BMAL1/GPX4 axis may be a potentially novel pathway for ferroptosis. Our work may offer a fresh perspective for toxicological research examining the interactions between food pollutants, circadian clock, and ferroptosis.