Plin4 modulates lipid droplet accumulation and ferroptosis in neurons exposed to benzo[a]pyrene.

IF 7 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-10-06 DOI:10.1038/s41420-025-02747-8

Hongyu Sun, Zhirui Ma, Xingdi Guo, Jie Chen, Hui He, Xiaomin Tong, Tingyu Ji, Shihan Ding, Chaoli Zhou, Yi Lyu, Fengjie Tian, Jinping Zheng

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引用次数: 0

Abstract

Benzo[a]pyrene (B[a]P), an environmental neurotoxin, induces cognitive decline through ferroptosis-mediated mechanisms. Transcriptomic analysis (GSE75206) of B[a]P-exposed mouse hippocampus identified 1668 differentially expressed genes, with Plin4 emerging as a key regulator linked to ferroptosis and lipid droplet (LD) accumulation. Behavioral tests confirmed hippocampal-dependent cognitive impairment and Plin4 upregulation. Molecular analyses demonstrated ferroptosis activation, evidenced by altered expression of related genes (Gpx4, Slc7a11, Ptgs2) and biochemical markers of lipid peroxidation and iron imbalance. In HT22 cells, Benzopyrene-7,8-Diol-9,10-Epoxide (BPDE) dose-dependently elevated Plin4 expression, inducing mitochondrial damage and ferroptosis. Silencing Plin4 reversed BPDE-induced ferroptosis by restoring redox balance, reducing LD accumulation, and improving mitochondrial integrity. Mechanistically, Plin4 amplifies B[a]P neurotoxicity by exacerbating iron overload and LD accumulation, sensitizing neurons to ferroptosis. This study identifies Plin4 as a central mediator of environmental pollutant-induced neurodegeneration and proposes it as a therapeutic target for ferroptosis-related cognitive disorders.

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Plin4调节暴露于苯并[a]芘的神经元的脂滴积累和铁下垂。

苯并[a]芘（B[a]P）是一种环境神经毒素，通过铁中毒介导的机制导致认知能力下降。B[a] p暴露小鼠海马的转录组学分析（GSE75206）鉴定出1668个差异表达基因，其中Plin4是与铁死亡和脂滴（LD）积累相关的关键调节因子。行为测试证实海马依赖性认知障碍和Plin4上调。分子分析表明，相关基因（Gpx4, Slc7a11, Ptgs2）以及脂质过氧化和铁失衡的生化标志物的表达改变证明了铁下垂活化。在HT22细胞中，苯并芘-7,8-二醇-9,10-环氧化物（BPDE）剂量依赖性地升高Plin4的表达，诱导线粒体损伤和铁凋亡。沉默Plin4可通过恢复氧化还原平衡、减少LD积累和改善线粒体完整性来逆转bpde诱导的铁下垂。从机制上讲，Plin4通过加剧铁超载和LD积累，使神经元对铁凋亡敏感，从而增强B[a]P神经毒性。本研究确定Plin4是环境污染物诱导的神经变性的中心介质，并提出它作为铁中毒相关认知障碍的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.