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FOXO1

FOXO1

Overview

FOXO1 (forkhead box protein O1) is a transcription factor in the forkhead box O family that regulates gene expression programs involved in metabolism, stress resistance, cell survival, differentiation, and immune function. As a nuclear transcriptional regulator, FOXO1 integrates upstream signaling cues from pathways such as PI3K/AKT and sirtuin 1, and its activity is strongly influenced by subcellular localization, including nuclear translocation.

In biomedical research, FOXO1 is widely studied as a context-dependent regulator in cancer, metabolic disease, cardiovascular injury, neurodegeneration, and aging. Depending on cell type and disease setting, FOXO1 can support tumor suppression, T cell stem-like differentiation, energy metabolism, autophagy, and geroprotective programs, while dysregulated FOXO1 signaling has also been linked to inflammatory and degenerative phenotypes.

Focus of Latest Publications

Recent studies have examined FOXO1 as both a mechanistic node and a therapeutic target across diverse disease models. In Alzheimer’s disease-associated astrocyte dysfunction, ghrelin was reported to ameliorate pathology through uncoupling protein 2 (UCP2)-mediated inhibition of FOXO1 nuclear translocation, indicating that FOXO1 localization may be a key determinant of astrocyte responses in neurodegeneration. In a related neuroinflammatory context, miR-144 overexpression in type 2 diabetes mellitus mice suppressed FoxO1 and AdipoR1/AdipoR2 expression, promoted microglial M1 polarization, activated NLRP3 inflammasome-associated neuroinflammatory signaling, and increased Tau phosphorylation, linking FOXO1 to cognitive dysfunction and inflammatory brain injury.

FOXO1 was also investigated as a therapeutic target in corneal endothelial dysfunction, where multi-omics analysis identified it as a central and under-explored target, and an AAV-Foxo1 delivery system was developed to restore mitochondria-ER contacts. In cardiovascular disease, Yangxinshi Tablet was reported to improve post-myocardial infarction heart failure with reduced ejection fraction by inhibiting FOXO1/PDK4 signaling, thereby promoting the tricarboxylic acid cycle and increasing ATP production to restore energy metabolism. This aligns with broader evidence that FOXO1 participates in metabolic control, including regulation of pyruvate dehydrogenase kinase 4 and energy substrate utilization.

In cancer-related research, FOXO1 has been framed as a tumor-suppressive and immune-regulatory transcription factor. A study in metastatic renal cell carcinoma evaluated FOXO1 as a biomarker of improved response to immune checkpoint plus tyrosine kinase inhibitor therapy, emphasizing its clinical and immunological significance in RCC. In non-small cell lung cancer, nobiletin combined with vorinostat increased FOXO1 expression and LC3A/BII, contributing to autophagy induction in A549 cells. Another study reported that compounds identified by screening inhibited FOXO1/3a activity and suppressed dexamethasone-induced atrogin1 expression in C2C12 myoblasts, supporting a role for FOXO1 in muscle catabolic signaling. In breast cancer, optical redox imaging studies noted upregulation of FOXO1 alongside SIRT1, consistent with redox-linked signaling changes associated with NAD+/NADH balance.

FOXO1 has also been linked to immune cell differentiation and aging. Ponatinib was reported to inhibit LCK and PI3K signaling, enhancing the transcriptional functions of TCF7 and FOXO1 and promoting CD8+ T stem cell memory cell development. In primate epididymal aging, FOXO1 was markedly downregulated in progenitor cells, and restoration of a FOXO1 geroprotective pathway via seno-resistant mesenchymal progenitor cells alleviated aging-associated changes. Together, these studies reinforce FOXO1 as a multifunctional transcription factor at the intersection of metabolism, immunity, autophagy, senescence, and tissue homeostasis.

Key Publications

  • May Ghrelin Ameliorates Alzheimer's Disease-Associated Astrocyte Dysfunction via UCP2-Mediated Inhibition of FOXO1 Nuclear Translocation. (Molecular neurobiology, 2026, PMID 42185568): "Mechanistically, ghrelin upregulated uncoupling protein 2 (UCP2), which inhibited forkhead box protein O1 (FOXO1) nuclear translocation."
  • May Compounds identified by screening that inhibit the activity of transcription factor FOXO1/3a suppress dexamethasone-induced atrogin1 expression in C2C12 myoblasts. (Bioscience, biotechnology, and biochemistry, 2026, PMID 41790122): "...that inhibit the activity of transcription factor FOXO1/3a..."
  • May MiR-144 Regulates Cognitive Dysfunction via NLRP3 Inflammasome and FoxO1/AdipoR Pathway in T2DM Mice. (Molecular neurobiology, 2026, PMID 42086968): "Additionally, miR-144 overexpression significantly suppressed FoxO1 and AdipoR1/AdipoR2 expression while inducing microglial M1 polarization, activating downstream NLRP3-mediated neuroinflammatory responses, and increasing Tau phosphorylation."
  • May A Viscous DES-AAV-Foxo1 Delivery System With High Transfection Efficiency for the Treatment of Corneal Endothelial Dysfunction by Restoring Mitochondria-ER Contacts. (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026, PMID 42070230): "To address this, we first employed multi-omics analysis and identified FOXO1 as a central and under-explored therapeutic target for corneal endothelial dysfunction."
  • May Optical Redox Imaging of Breast Cancer NADH Redox Status Associated with PGC1α Gene Expression. (Academic radiology, 2026, PMID 42055667): "Important signaling regulating genes SIRT1 and FOXO1 were upregulated, whose activities influence the NAD+/NADH ratio or are influenced by the NAD+/NADH ratio."
  • May Nobiletin inhibits non-small cell lung cancer through TRKC and exhibits a synergistic effect with the HDAC inhibitor. (Chinese journal of natural medicines, 2026, PMID 42062032): "Furthermore, the combination of nobiletin and vorinostat enhanced the expression of LC3A/BII and forkhead box O1 (FOXO1), ultimately inducing autophagy in A549 cells."
  • May Yangxinshi Tablet protects against post-myocardial infarction heart failure with reduced ejection fraction by improving energy metabolism through inhibition of FOXO1/PDK4 signaling. (Chinese journal of natural medicines, 2026, PMID 42062031): "Notably, YXS ameliorated post-MI HF by inhibiting forkhead box O1 (FOXO1)/pyruvate dehydrogenase kinase 4 (PDK4) signaling, thereby promoting the tricarboxylic acid (TCA) cycle and increasing adenosine 5'-triphosphate (ATP) levels to restore energy metabolism both in vivo and in vitro."
  • Apr Clinical and immunological significance of FOXO1 as a biomarker of improved response to immune checkpoint plus tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma. (European journal of pharmacology, 2026, PMID 41935603): "Forkhead box protein O1 (FOXO1) is a key transcription factor regulating tumor suppression and T cell immunity, but its clinical and immunological significance in RCC is unclear."
  • Apr Ponatinib inhibits LCK and PI3K signaling and promotes CD8+ T stem cell memory cell development. (Nature communications, 2026, PMID 41946709): "ponatinib inhibits LCK and PI3K signaling to enhance the transcriptional functions of TCF7 and FOXO1, thereby promoting CD8+ TSCM cell differentiation."
  • Apr Restoring the FOXO1 geroprotective pathway via seno-resistant mesenchymal progenitor cells alleviates primate epididymal aging. (Protein & cell, 2026, PMID 41875394): "Within PCs, the longevity-associated transcription factor FOXO1 was markedly downregulated with age."
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