KLF15 prevents ferroptosis in vascular smooth muscle cells via interacting with p53

Abstract

The formation of intracranial aneurysm (IA) is intimately linked to the progressive loss of vascular smooth muscle cells (VSMCs). Reactive oxygen species (ROS) play a pivotal role in inducing VSMC death during IA progression. Krüppel-like factor 15 (KLF15) plays a crucial role in preserving vascular homeostasis. However, the potential impact of KLF15 on ROS-triggered VSMC death remains unexplored. Analysis of microarray datasets from the GEO database suggests reduced KLF15 levels in human IA tissues. This study further confirms decreased KLF15 expression in ROS-treated human brain VSMCs (HBVSMCs). An unbiased examination of the transcriptome in HBVSMCs transfected with siKLF15 reveals that KLF15 regulates the ferroptosis pathway upon ROS stress. Silencing KLF15 results in the upregulation of genes promoting ferroptosis, such as SAT1, HMOX1, and MAP1LC3B, while downregulation of the ferroptosis regulatory gene SLC7A11. Cell death increases in KLF15-silenced HBVSMCs and is rescued by the ferroptosis inhibitor frerrostain-1. Co-immunoprecipitation and in situ proximity ligation assay indicate that KLF15 interacts with p53. Knockdown of p53 rescues the effects of siKLF15 on ROS-induced ferroptosis, including elevated cell death, lipid ROS levels, and the malondialdehyde content, as well as reduced SLC7A11protin levels in HBVSMCs. These findings suggest that KLF15 may lower cell sensitivity to ferroptosis by interacting with p53 and preventing p53-mediated transcriptional repression of SLC7A11. Overall, our results reveal a protective function of KLF15 in preventing ROS-induced ferroptosis in HBVSMCs.