Inhibition of the p62-Nrf2-GPX4 Pathway Confers Sensitivity to Butachlor-Induced Splenic Macrophage Ferroptosis.
Yi ZhaoShang-Jia YangYi-Feng HuangFu-Wei JiangHong-Li SiMing-Shan ChenJia-Xin WangShuo LiuYu-Jun JiangJin-Long LiPublished in: Journal of agricultural and food chemistry (2024)
Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.
Keyphrases
- cell death
- oxidative stress
- nuclear factor
- diabetic rats
- public health
- cell cycle arrest
- adipose tissue
- toll like receptor
- protein protein
- poor prognosis
- climate change
- fatty acid
- signaling pathway
- fluorescent probe
- high glucose
- risk assessment
- binding protein
- quantum dots
- endoplasmic reticulum stress
- long non coding rna
- real time pcr