SIRT1-FOXO3 Pathway reprograms fatty acid metabolism to Mitigate Ferroptosis and Fibrosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1240308 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32810892.fastq.gz | Fastqsanger.gz | |||
| SRR32810893.fastq.gz | Fastqsanger.gz | |||
| SRR32810894.fastq.gz | Fastqsanger.gz | |||
| SRR32810895.fastq.gz | Fastqsanger.gz | |||
| SRR32810896.fastq.gz | Fastqsanger.gz |
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Project description:Targeting ferroptosis with reductive agents has emerged as a promising strategy to mitigate fibrotic diseases in various pathological conditions. However, while the NAD+/NADH redox pair plays a crucial role in biological processes, its connection to ferroptosis beyond FSP1 remains poorly understood. To explore underappreciated NAD+/NADH-dependent factors in the ferroptosis cascade, we conducted a compound screening of 138 NAD+ enzyme modulatory molecules and identified Sirtuin-1 (SIRT1) activators as critical regulators of ferroptosis. SIRT1 activators, such as SRT1720, broadly inhibit ferroptosis by reducing lipid peroxidation without affecting labile iron levels. Moreover, SRT1720 effectively alleviates pulmonary and liver fibrosis in mouse models. Using ChIP-seq and validation assays, we demonstrated that FOXO3 binds to gene loci involved in fatty acid elongation and arachidonic acid metabolism in ferroptosis. SRT1720 disrupts this binding, thereby restraining fatty acid metabolism and limiting lipid peroxides production. Our findings establish the SIRT1-FOXO3 axis as a key inhibitory pathway against ferroptosis and highlight its therapeutic potential for ferroptosis-associated diseases, including fibrosis.
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Project description:SIRT1-FOXO3 Pathway reprograms fatty acid metabolism to Mitigate Ferroptosis and Fibrosis [ChIP-seq]
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Project description:SIRT1 deacetylase functions in a variety of cells and tissues to mitigate age- and disease-induced damages. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor units, and specifically alpha-motor neurons, with advancing age and during the progression of amyotrophic lateral sclerosis (ALS). Here, we show that SIRT1 expression decreases in the spinal cord of wild type mice with advancing age. Using mouse models that overexpress or inactivate SIRT1 in motor neurons, we discovered that SIRT1 prevents age-related degeneration of motor neurons’ presynaptic sites at neuromuscular junctions (NMJs). We also found that increasing SIRT1 in motor neurons delays degeneration of presynaptic sites at NMJs and extends the lifespan of SOD1G93A mice. Thus, SIRT1 has a similar effect on aging and ALS-affected motor neurons, two conditions in which a remarkable number of transcripts are similarly altered in the spinal cord. These include genes involved in inflammatory and immune responses and genes with known function at synapses. These findings show that SIRT1 functions to mitigate pathological changes induced by aging and ALS, two conditions with a surprising degree of overlap in the spinal cord.
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