Exploring the toxicological network of bleomycin-induced pulmonary fibrosis: The role of long non-coding RNAs

IF 3.5 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY
Bingxin Li, Hongbin Shi, Yun Ma, Ruining Zhao, Haijun Zhang
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引用次数: 0

Abstract

Bleomycin (BLM) is an effective anticancer agent; however, its clinical use is limited by its tendency to induce pulmonary fibrosis (PF), a complication whose molecular mechanisms remain unclear. In this study, we established a BLM-induced C57BL/6 mouse model of PF and applied total RNA-seq in combination with network toxicology approaches to investigate the role of long noncoding RNAs (lncRNAs) in this process. The lncRNA Xist was identified as a hub node in the network, regulating the expression of its target Mmp25 via interaction with miR-34a-5p and miR-449c-5p. Further Gene Ontology and KEGG pathway analyses suggested that BLM may promote PF by modulating the TGF-β signaling pathway. Importantly, siRNA-mediated knockdown of Xist in vitro significantly attenuated BLM-induced cellular injury and suppressed TGF-β pathway activation, confirming its functional involvement. These findings provide novel insights into the molecular basis of BLM-induced PF from an lncRNA perspective and highlight Xist as a potential therapeutic target for mitigating the drug's pulmonary toxicity.
探索博莱霉素诱导肺纤维化的毒理学网络:长链非编码rna的作用
博来霉素(BLM)是一种有效的抗癌药物;然而,其临床应用受到其诱导肺纤维化(PF)倾向的限制,这是一种分子机制尚不清楚的并发症。在本研究中,我们建立了blm诱导的PF小鼠C57BL/6模型,并应用总RNA-seq结合网络毒理学方法研究了长链非编码rna (lncRNAs)在这一过程中的作用。lncRNA Xist被确定为网络中的枢纽节点,通过与miR-34a-5p和miR-449c-5p相互作用调节其靶蛋白Mmp25的表达。进一步的Gene Ontology和KEGG通路分析表明,BLM可能通过调节TGF-β信号通路促进PF的发生。重要的是,sirna介导的Xist体外敲低可显著减轻blm诱导的细胞损伤,抑制TGF-β通路的激活,证实其功能参与。这些发现从lncRNA的角度对blm诱导的PF的分子基础提供了新的见解,并突出了Xist作为减轻药物肺毒性的潜在治疗靶点。
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来源期刊
Food and Chemical Toxicology
Food and Chemical Toxicology 工程技术-毒理学
CiteScore
10.90
自引率
4.70%
发文量
651
审稿时长
31 days
期刊介绍: Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.
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