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Results for “FOXO3”

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PubMed2025

Multiplexed Dual-Color Fluorescence-Based Distinction Between Nuclear Trapping and Translocation of FOXO3.

FOXO3 is a transcription factor that mainly exerts its functions in the cell nucleus. The amino acid sequence of FOXO3 contains a nuclear localization sequence (NLS) and a nuclear export sequence (NES) allowing for nuclear/cytoplasmic shuttling that plays an important role in regulating FOXO3 activity. Nuclear accumulation of FOXO3 proteins can be the result of translocation to the nucleus triggered by upstream regulatory input or trapping of FOXO3 within the nucleus through the inhibition of its nuclear export via the receptor CRM1. In order to distinguish these two modes of FOXO3 activation, we have generated a multiplexed assay. The development of this platform includes a reporter cell line that monitors CRM1 activity by using RFP-labeled HIV-1 Rev. protein with a strong heterologous NES. Simultaneously, the intracellular localization of FOXO3 can be monitored by a second cell line stably expressing GFP-FOXO3. Here we describe a detailed protocol on how to co-culture these reporter cell lines and use them to interrogate compound-induced FOXO3 activation in order to understand the mode of action.

Forkhead Box Protein O3↗

PubMed2026

UNCX/SIN3A-Mediated H4K8 decrotonylation suppresses FOXO3 to drive TNBC progression and docetaxel resistance.

Triple-negative breast cancer (TNBC) remains a clinically challenging subtype characterized by aggressive behavior and limited treatment options. Though docetaxel remains a cornerstone chemotherapy for TNBC, the frequent emergence of resistance highlights the urgent need to identify novel therapeutic targets. In this study, we report that uncoordinated homeobox (UNCX) is upregulated in docetaxel-resistant breast cancer cells, genomically amplified in breast cancer, and associated with poor survival in breast carcinoma patients. Functional studies revealed that UNCX promotes breast cancer cell proliferation, migration and reduces the docetaxel sensitivity. Mechanistically, UNCX functions as a transcriptional repressor by recruiting the SIN3A complex. Genome-wide profiling indicated that the UNCX/SIN3A complex directly binds to the promoters of tumor-suppressor genes including FOXO3, and represses their transcription by removing histone H4K8 crotonylation (H4K8cr). Additionally, the UNCX/SIN3A complex enhances FOXO3 phosphorylation and inhibits its nuclear translocation, further inhibiting its activity. Notably, SIN3A knockdown, FOXO3 overexpression, or crotonylation restoration effectively reverses UNCX-induced malignant phenotypes. These findings collectively establish the UNCX/SIN3A-H4K8cr-FOXO3 axis as a pivotal epigenetic regulator of TNBC progression and chemoresistance, revealing new avenues for targeted therapeutic development against this aggressive breast cancer subtype.

Humans↗

PubMed2026

Novel genetic variants identification and immune profiling in ataxia telangiectasia patients.

BACKGROUND: Ataxia telangiectasia (AT) is an autosomal recessive neurodegenerative disease. While heterozygous relatives of AT patients are known to be clinically healthy, a predisposition to various pathologies has been reported. Our aim was firstly, to further characterize the clinical features and broaden the spectrum of genetic pathogenic variants in AT patients. Secondly, we aimed to study the immune profiles of AT patients and their relatives to identify similarities or common biomarkers. METHODS: A Target Gene Sequencing for six patients suspected with AT was performed. Computational analysis was conducted to assess the pathogenicity of novel variants. The distribution of immune cells was assessed by flow cytometry in patients with AT, AT-like disorder, Friedreich ataxia, and in AT relatives. The expression pattern of candidate genes was evaluated by RT-qPCR. RESULTS: We identified and predicted the pathogenicity of novel variants in the ATM gene. Computational analysis suggested that the novel identified missense mutation could affect ATP binding pattern and ATM protein flexibility, while Alu element insertion could probably induces a premature stop codon. Furthermore, our results confirm the pathogenic effect of identified splicing mutations on the ATM transcript. Moreover, we noticed a high percentage of LTCD4 + and LTCD8 + senescent subsets in AT patients and a relative increase of the of intermediate and non-classical monocytes accompanied with a decrease of classical monocytes specifically in AT patients with truncated biallelic mutations which was intriguingly similar to the immune profile of AT parents. In addition, a difference of immune pattern was observed between AT patients with biallelic truncated mutations compared to those with at least one non-truncated mutation, with a variability intragroup. Gene expression analysis identified FOXO3, IL33 and METTL3 as putative genes that may yield clues into AT pathogenesis. CONCLUSION: Taken together, our study expands the mutational spectrum of AT disease worldwide and further characterize the immune profile of AT patients uncovering a possible difference in some immune cellular subsets related to ATM mutation type and delineate putative immune abnormalities related to ATM heterozygosity among AT parents. Furthermore, dysregulation in FOXO3, IL33 and METTL3 expression could be related to disease severity.

Humans↗

PubMed2025

Measuring FOXO Activity by Using qPCR-Based Expression Analysis of FOXO Target Genes.

FOXO transcription factors belong to the forkhead protein family and are distinguished by their unique forkhead (FKH) DNA-binding domain. In the realm of mammals, four FOXO paralogs are recognized: FOXO1, FOXO3, FOXO4, and FOXO6. These paralogs are evolutionary counterparts of the daf-16 gene discovered in the nematode C. elegans. A key feature shared by these paralogs is a consensus binding site known as the DAF-16 family protein-binding site (DBE: 5'-TTGTTTAC-3'). The functional outcome of FOXO transcription factors primarily hinges on their affinity for these specific binding sites within the promoters of their target genes. Nevertheless, it is worth noting that many of these target genes exhibit tissue-specific expression patterns. Consequently, there is not a single FOXO target gene whose expression can reliably serve as a universal indicator of FOXO activity across all cell types and tissues or in response to all stimuli. In light of these considerations, we present a collection of target genes that, when collectively assessed, can accurately gauge FOXO activation. In this chapter, we outline a specific protocol for utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure the expression levels of these genes.

Forkhead Transcription Factors↗

PubMed2025

The pathway of autophagy in the epigenetic landscape of Mycobacterium-host interactions.

Macroautophagy (autophagy) is an evolutionarily conserved process that degrades excess cytoplasmic components, such as protein aggregates and damaged organelles, by encapsulating them within double-membrane autophagosomes. These autophagosomes undergo distinct stages - initiation, phagophore nucleation, expansion, and closure - before fusing with lysosomes (or occasionally endosomes) for degradation and recycling. This process is regulated by ATG (autophagy related) proteins, which govern autophagosome formation and lysosomal fusion. Epigenetic modifications and transcription factors can regulate ATG gene expression in the nucleus. Autophagy also plays a key role in eliminating intracellular Mycobacterium tuberculosis (Mtb) through the lytic and antimicrobial activities of autolysosomes, which are more potent antimicrobial compartments than conventional phagosomes. Emerging evidence suggests that Mtb can modify the host epigenome and transcriptional machinery, significantly affecting the host immune response. This review explores the epigenetic regulation of autophagy during mycobacterium-host interactions. The interplay between epigenetic regulation and autophagy highlights a crucial aspect of host-pathogen interactions during Mtb infection. Understanding how Mtb manipulates the host epigenome to regulate autophagy could lead to the development of novel therapeutic strategies that enhance autophagic pathways or counteract Mtb's immune evasion tactics.Abbreviations: AM: Alveolar macrophages; ATG: autophagy related; DNMT: DNA methyltransferase; FOXO3: forkhead box O3; HAT: histone acetyltransferase; HDAC: histone deacetylase; MIR: microRNA; MTOR: mechanistic target of rapamycin kinase; Mtb: Mycobacterium tuberculosis; ROS: reactive oxygen species; SIRT: sirtuin; STPK: serine/threonine protein kinase.

Autophagy↗

PubMed2025

Silencing FAF2 mitigates alcohol-induced hepatic steatosis by modulating lipolysis and PCSK9 pathway.

BACKGROUND: Chronic alcohol consumption leads to lipid accumulation, oxidative stress, cellular damage, and inflammation in the liver, collectively referred to as alcohol-associated liver disease (ALD). FAF2/UBXD8/ETEA (Fas-associated factor 2) is a ubiquitin ligase adaptor protein that plays a crucial role in the ubiquitin-mediated degradation of misfolded proteins in the endoplasmic reticulum. A recent genome-wide association study indicated an association between FAF2 and ALD; however, the exact contribution of FAF2 to ALD pathogenesis remains unclear. METHODS: FAF2 was knocked down using AAV-delivered shRNA in C57/BL6 mice. Mice were subjected to a chronic-plus-single binge ethanol feeding (NIAAA) model. Nine hours after gavage, liver, blood, and other organs of interest were collected for gene expression and biochemical analyses. RESULTS: We first observed a significant elevation in hepatic FAF2 protein expression in individuals with ALD and in mice subjected to an ethanol-binge model. Interestingly, knocking down FAF2 in the liver using adeno-associated virus serotype 8-delivered short hairpin RNA conferred a protective effect against alcohol-induced liver steatosis in ethanol-binged mice. Transcriptomic analysis revealed that differentially expressed genes were enriched in multiple lipid metabolism regulation pathways. Further analysis of transcription factors regulating these differentially expressed genes suggested potential regulation by SREBP1. Several SREBP1 target genes, including Fasn, Scd1, Lpin1, and Pcsk9 (proprotein convertase subtilisin/kexin type 9), were dysregulated in the livers of ethanol-fed FAF2 knockdown mice. Additionally, Pcsk9 could be regulated through the FOXO3-SIRT6 pathway in the livers of ethanol-fed FAF2 knockdown mice, leading to increased liver low-density lipoprotein receptor expression and reduced plasma LDL cholesterol levels. Furthermore, FAF2 knockdown in mouse liver enhanced adipose triglyceride lipase lipolytic activity by upregulating the adipose triglyceride lipase activator, comparative gene identification-58, and downregulating the adipose triglyceridelipase transport inhibitor, Elmod2, contributing to the alleviation of liver steatosis. CONCLUSIONS: Our study uncovers a novel mechanism involving FAF2 in the pathogenesis of ALD.

Animals↗

PubMed2026

Multi-omics unveils seasonal remodeling and metabolic crosstalk between testis and abdominal fat body in a non-amplexus stream frog Nanorana taihangnica (Anura: Dicroglossidae).

BACKGROUND: Energy allocation between reproduction and survival represents a fundamental life-history challenge for animals in seasonal environments. Using integrated transcriptomics and metabolomics, we investigated Nanorana taihangnica (Anura: Dicroglossidae), a non-amplexus stream frog endemic to China, to elucidate the seasonal morphological and molecular coordination between the testis and abdominal fat body. RESULTS: Morphological analysis showed that fat body adipocyte cross-sectional area minimized at the end of the breeding season but rapidly recovered thereafter, while testicular volume continued declining post-breeding and only recovered during the non-breeding period. During breeding season, multi-omics analyses revealed that the fat body enhanced fatty acid oxidation, upregulated histidine-carnosine metabolism, activated NAD+ metabolism and FOXO3-mediated antioxidative responses to mitigate metabolic stress, and regulated adipocyte survival and apoptosis via sphingolipid signaling. Seasonal testicular development was centrally regulated by the mTOR signaling pathway, whose activity integrated autophagy levels, NAD+ availability, and aspartate metabolism to coordinate spermatogonial proliferation and spermatogenesis. CONCLUSIONS: This study demonstrates that N. taihangnica optimizes seasonal energy storage, allocation, and reproductive investment through molecular and metabolic crosstalk between the fat body and testis, providing empirical insights into the physiological integration of life-history strategies in animals inhabiting fluctuating environments.

Animals↗

PubMed2026

Research progress on multi-mechanism analysis and protection strategies of ovarian aging and fertility decline.

Age-related fertility decline is an increasingly important challenge in reproductive medicine, driven largely by progressive ovarian aging. The aging ovary undergoes functional deterioration characterized by reduced ovarian reserve and declining oocyte quality, ultimately limiting female reproductive lifespan. Although multiple molecular and cellular processes associated with ovarian aging have been identified, these mechanisms are often discussed independently, limiting an integrated understanding of how they interact within the ovary. In this review, we propose an ovary-centered, multi-mechanistic framework to organize current evidence on ovarian aging and fertility decline. We discuss how genomic instability, telomere attrition, mitochondrial dysfunction, oxidative stress, chronic cellular stress responses, and alterations in ovarian signaling and microenvironmental homeostasis collectively contribute to follicle depletion and impaired oocyte competence. Particular emphasis is placed on signaling pathways involved in follicle activation and stress adaptation, including PI3K/AKT/mTOR, FOXO3, Hippo, and AMPK-Sirtuin networks, while acknowledging that many mechanistic relationships remain incompletely defined in physiological ovarian aging. Building on this integrative perspective, we further evaluate mechanism-oriented intervention strategies, including mitigation of cellular stress, metabolic and signaling modulation, optimization of the ovarian microenvironment, established fertility preservation technologies, and emerging exploratory approaches. By integrating current mechanistic and translational evidence, this review provides a conceptual framework for understanding ovarian aging and highlights future directions for evidence-based fertility preservation and reproductive health management in the context of aging.

Humans↗