Butylparaben exposure induces renal fibrosis through Ncoa4-mediated ferroptosis
Butylparaben (BuP), is a widely used synthetic preservative extensively applied in cosmetics and pharmaceuticals. Previous studies have confirmed that butylparaben induces glomerular and tubular damage in HEK293T cells and zebrafish by triggering oxidative stress, lipid peroxidation, and downregulating the PI3K-AKT pathway. However, the effects of BuP exposure on mammalian kidneys have not been fully elucidated. Renal fibrosis is a common pathological change in the progression of various primary and secondary kidney diseases to end-stage renal disease. In this study, we uncovered that BuP exposure induced renal fibrosis in the kidneys. RNA sequencing revealed that ferroptosis-related genes were highly enriched in the kidneys after BuP treatment. Further, western blot and immunofluorescence experiments confirmed significant alterations of ferroptosis-related proteins after BuP exposure. We confirmed that butylparaben exposure increased ROS levels and promoted lipid peroxidation. Additionally, we observed that BuP treatment led to reduced mitochondrial volume, and disrupted mitochondrial membrane potential. Further mechanistic studies revealed that BuP promotes NCOA4 expression, driving ferritinophagy and resulting in elevated Fe2+ levels, thereby inducing ferroptosis. Both ferroptosis inhibitors and knockdown of the Ncoa4 gene significantly alleviated butylparaben-induced renal fibrosis. This study is the first to reveal that butylparaben induces renal fibrosis through a novel mechanism involving the activation of Ncoa4 and ferritinophagy, leading to ferroptosis. This provides an important theoretical basis for evaluating the nephrotoxicity of BuP.