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Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products

ABSTRACT: Ferroptosis, a newly discovered form of regulatory cell death (RCD), has been demonstrated to be distinct from other types of RCD, such as apoptosis, necroptosis, and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation and oxidative perturbation, and is inhibited by iron chelators and lipophilic antioxidants. This process is regulated by specific pathways and is implicated in diverse biological contexts, mainly including iron homeostasis, lipid metabolism, and glutathione metabolism. A large body of evidence suggests that ferroptosis is interrelated with various physiological and pathological processes, including tumor progression (neuro)degenerative diseases, and hepatic and renal failure. There is an urgent need for the discovery of novel effective ferroptosis-modulating compounds, even though some experimental reagents and approved clinical drugs have been well documented to have anti- or pro-ferroptotic properties. This review outlines recent advances in molecular mechanisms of the ferroptotic death process and discusses its multiple roles in diverse pathophysiological contexts. Furthermore, we summarize chemical compounds and natural products, that act as inducers or inhibitors of ferroptosis in the prevention and treatment of various diseases. Herein, it is particularly highlighted that natural products show promising prospects in ferroptosis-associated (adjuvant) therapy with unique advantages of having multiple components, multiple biotargets and slight side effects.

SUBMITTER: Ge C

PROVIDER: S-EPMC8804219 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products

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