Uncovering ferroptosis in Parkinson's disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products

Peng Wang; Qi Chen; Zhuqian Tang; Liang Wang; Bizhen Gong; Min Li; Shaodan Li; Minghui Yang

doi:10.3389/fgene.2023.1231707

Uncovering ferroptosis in Parkinson's disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products

Front Genet. 2023 Jul 6:14:1231707. doi: 10.3389/fgene.2023.1231707. eCollection 2023.

Authors

Peng Wang^{1

2}, Qi Chen², Zhuqian Tang³, Liang Wang⁴, Bizhen Gong^{1

2}, Min Li², Shaodan Li², Minghui Yang²

Affiliations

¹ Postgraduate School, Medical School of Chinese PLA, Beijing, China.
² Department of Traditional Chinese Medicine, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China.
³ School of Pharmacy, Key Laboratory for Modern Research of Traditional Chinese Medicine of Jiangsu, Nanjing University of Chinese Medicine, Nan Jing, Jiangsu, China.
⁴ Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.

Abstract

Objective: Ferroptosis, a novel form of cell death, is closely associated with excessive iron accumulated within the substantia nigra in Parkinson's disease (PD). Despite extensive research, the underlying molecular mechanisms driving ferroptosis in PD remain elusive. Here, we employed a bioinformatics and machine learning approach to predict the genes associated with ferroptosis in PD and investigate the interactions between natural products and their active ingredients with these genes. Methods: We comprehensively analyzed differentially expressed genes (DEGs) for ferroptosis associated with PD (PDFerDEGs) by pairing 3 datasets (GSE7621, GSE20146, and GSE202665) from the NCBI GEO database and the FerrDb V2 database. A machine learning approach was then used to screen PDFerDEGs for signature genes. We mined the interacted natural product components based on screened signature genes. Finally, we mapped a network combined with ingredients and signature genes, then carried out molecular docking validation of core ingredients and targets to uncover potential therapeutic targets and ingredients for PD. Results: We identified 109 PDFerDEGs that were significantly enriched in biological processes and KEGG pathways associated with ferroptosis (including iron ion homeostasis, iron ion transport and ferroptosis, etc.). We obtained 29 overlapping genes and identified 6 hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2) by screening with two machine learning algorithms. Based on this, we screened 263 natural product components and subsequently mapped the "Overlapping Genes-Ingredients" network. According to the network, top 5 core active ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) were molecularly docked to hub genes to reveal their potential role in the treatment of ferroptosis in PD. Conclusion: Our findings suggested that PDFerDEGs are associated with ferroptosis and play a role in the progression of PD. Taken together, core ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) bind well to hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2), highlighting novel biomarkers for PD.

Keywords: Parkinson’s disease; ferroptosis; ingredient; machine learning; natural product; transcriptomics.

Grants and funding

This research was funded by the National Natural Science Foundation of China, Grant No. 82130117; the Inheritance and Innovation of TCM “Hundreds, Thousands, Tens of Thousands” Talent Project Qihuang Scholars Fund [(2018)12].