Search Results (160)

Diabetes mellitus (DM) induces significant endocrine disruption and oxidative stress (OS) within the testes, resulting in impaired spermatogenesis, increased sperm abnormalities, and compromised reproductive function. This study aimed to evaluate the combined protective effects of Semaglutide (SEM) combined with Carica papaya (papaya) juice against type 2 diabetes-induced testicular damage in rats. Forty adult male albino rats were divided into four experimental groups: a control group, a Streptozotocin (STZ)-induced diabetic group, a diabetic group treated with SEM (0.3 mg/kg), and a diabetic group treated with SEM (0.3 mg/kg) in combination with 10% papaya juice, administered for eight weeks. Statistically significant superiority over SEM alone was observed for selected endpoints; the findings primarily support the potential of papaya as a dose-sparing adjunct rather than demonstrating uniformly enhanced efficacy. They significantly improved systemic metabolic parameters, as evidenced by reduced fasting blood glucose (FBG) and glycated hemoglobin (HbA_1c) levels and restoration of the lipid profile. Importantly, it also attenuated diabetes-induced testicular injury, as demonstrated by improved reproductive hormone levels, enhanced sperm parameters, restoration of antioxidant defenses, modulation of inflammatory and apoptotic signaling, and marked histopathological recovery of seminiferous tubular architecture. Antioxidant markers revealed a notable reduction in malondialdehyde (MDA) and cytochrome P450 2E1 (CYP2E1), along with significant increases in reduced glutathione, catalase (CAT), and superoxide dismutase (SOD). Furthermore, a marked modulation of key pro-inflammatory and pro-apoptotic mediators was observed, including forkhead box protein O1 (FOXO1), microRNA-155 (miR-155), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B cell subunit 1 (NF-κB1), interleukin-6 (IL-6), caspase-3 (CASP3), and BCL2-Associated X Apoptosis Regulator (Bax), while a significant upregulation of sirtuin-1 (SIRT1), microRNA-34c (miR-34c), and B-cell lymphoma-2 (Bcl-2) was also detected. Histopathological assessments confirmed the restoration of normal testicular architecture in the treated groups. These findings indicate that the combination strategy may have the potential to achieve dose savings while maintaining efficacy comparable to the standard-dose SEM, through the enhancement of the antioxidant defenses, modulation of inflammation, and apoptosis, specifically via the modulation of the miR-34c/miR-155 and SIRT1/FOXO1 signaling. Full article

Objective: Impaired fatty acid oxidation (FAO) is considered an important metabolic mechanism underlying skeletal muscle aging and sarcopenia; however, the key regulatory molecules involved in this process remain incompletely defined. This study aimed to identify candidate biomarkers associated with impaired FAO in aged skeletal muscle, characterize their potential biological functions and regulatory features through integrated bioinformatics and machine learning analyses, and preliminarily validate their expression patterns in in vivo and in vitro aging models. Methods: Skeletal muscle aging transcriptomic datasets GSE1428 and GSE674 were obtained from the Gene Expression Omnibus database. FAO-related genes were retrieved from GeneCards. Differentially expressed FAO-related genes (DE-FAOGs) were identified through differential expression analysis and were further analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Random forest, Boruta, and protein–protein interaction (PPI) network analyses were used to screen hub genes, and an artificial neural network (ANN) model was constructed. Single-cell RNA sequencing analysis, gene set enrichment analysis, ceRNA network construction, drug prediction, molecular docking, and molecular dynamics simulation were further performed. Hub gene expression was validated by qRT-PCR in naturally aged mice and D-galactose-induced senescent C2C12 cells. Results: A total of 69 DE-FAOGs were identified and were mainly enriched in mitochondrial function, electron transport chain, and energy metabolism-related pathways. Three hub genes, creatine kinase, mitochondrial 2 (CKMT2), actin alpha cardiac muscle 1 (ACTC1), and forkhead box O3 (FOXO3), were identified by random forest, Boruta, and PPI analyses. Receiver operating characteristic (ROC) analysis showed good discriminatory performance for these genes. The three-gene ANN model achieved area under the curve (AUC) values of 0.992 and 0.964 in the training and validation datasets, respectively. Gene set enrichment analysis (GSEA) suggested that the hub genes were closely associated with mitochondrial energy metabolism, lipid metabolism, and stress regulation. qRT-PCR confirmed decreased Ckmt2 expression and increased Actc1 and Foxo3 expression under aging conditions, consistent with the bioinformatics results. Conclusions: CKMT2, ACTC1, and FOXO3 are potential biomarkers associated with impaired FAO in aged skeletal muscle. The ANN model based on these three genes showed good predictive performance and may provide new insights into the metabolic mechanisms and therapeutic targets of sarcopenia. Full article

Objectives: The study aimed to evaluate the effects of full-fat rice bran (FFRB; Tainung No. 81, Taiwan) at various doses on insulin resistance, muscle atrophy, and gut microbiota composition in middle-aged ovariectomized (OVX) mice fed a high-fat diet (HFD), using young sham-operated mice as a life-stage reference group. Methods: Thirty-six female ICR mice were assigned to six groups, including OVX mice fed HFD with or without 5%, 10%, or 20% FFRB. Results: Compared with HFD-fed OVX controls, 20% FFRB reduced body weight gain by 43%, decreased visceral fat mass, and improved insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR reduced by 65%, P_trend = 0.001). FFRB attenuated the decline in relative grip strength (forelimb, P_trend = 0.013; four-limb, P_trend < 0.001), and upregulated muscle protein synthesis genes, including insulin receptor substrate 1 (IRS-1), mammalian target of rapamycin (mTOR), eukaryotic translation initiation factor 4E binding protein 1 (eIF-4EBP1), while downregulating forkhead box protein O1 (FOXO1), muscle RING-finger protein-1 (MuRF-1), and interleukin (IL)-6. FFRB was also associated with higher fecal acetate levels (P_trend < 0.001), upregulated colonic tight junction genes (occludin and zonula occludens (ZO)-1), and greater relative abundance of g_Muribaculum. Correlation analyses revealed positive associations between short-chain fatty acids (SCFAs) and muscle strength, muscle anabolic markers, genus Lachnospiraceae_UCG_001, and Muribaculum. Conclusions: Dietary inclusion of FFRB was associated with favorable metabolic and muscle-related parameters in HFD-fed middle-aged OVX mice, with potential involvement of gut microbiota and SCFA alterations. Full article

Myocardial infarction (MI) remains the leading cause of death globally. Current treatment strategies involve restoring blood flow to the coronary artery, but have shortcomings in that these procedures cannot reverse damage to the myocardium that has already occurred. Therefore, therapies that can decrease the severity of ischemic damage are needed. Oxidative stress is an early and major driver of cardiomyocyte death following MI. Rhynchophylline (RHY) is a natural alkaloid known for its antioxidant activity; however, whether it can protect against MI-induced ischemic injury, as well as its underlying mechanism of action, remains unexplored. We performed murine models of surgical MI and examined the effects and mechanisms of RHY in protecting against myocardial ischemic injury. A sirtuin 1 (SIRT1)-specific inhibitor, EX-527, was subsequently used to verify that the cardioprotective effects of RHY were dependent upon targeted SIRT1-activation. Mice administered with RHY significantly protected against ischemic injury following MI, with improved cardiac function, reduced infarct size, and decreased levels of oxidative and DNA damage. The cardioprotective effect of RHY is associated with activation of the SIRT1 and its downstream redox-sensitive transcription factors: nuclear factor erythroid 2-related factor 2 (NRF2) and forkhead-box protein O3 (FOXO3a). The cardioprotective and antioxidant effects of RHY were abolished by EX-527, a selective SIRT1 inhibitor. Our findings provide evidence for the robust antioxidant properties of RHY in protecting against MI injury via activating the SIRT1/NRF2/FOXO3a signaling axis. These findings provide new mechanistic insight into the preconditioning-like cardioprotective potential of RHY during myocardial infarction. Full article

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality, with poor survival outcomes despite advances in surgery, chemotherapy, targeted therapy, and immunotherapy. The tumor microenvironment (TME) plays a central role in sustaining tumor growth, immune evasion, and systemic metabolic dysfunction. In this study, we performed an integrative analysis of differentially expressed microRNAs (miRNAs) to uncover their contributions to dysregulated signaling networks in NSCLC. hsa-miR-486-5p was identified as a prominent differentially expressed candidate miRNA. Using mathematical modeling and regression-based reduction, we identified Forkhead Box O1 (FOXO1) and Unc-51 like Autophagy Activating Kinase 2 (ULK2) as critical regulatory nodes that integrate oncogenic signaling with cellular homeostasis. Aberrant expression of hsa-miR-486-5p was found to modulate pathways including PI3K/AKT/mTOR, NF-κB, and JAK-STAT3, thereby promoting tumor progression and secretion of inflammatory cytokines. These cytokines, viz., IL-6, TNF-α, and IL-1β, activate muscle-specific protein degradation pathways through E3 ubiquitin ligases TRIM63 and FBXO32, linking NSCLC progression to cancer-associated sarcopenia. Quasipotential landscape analysis further revealed dynamic phenotypic transitions between stable and unstable states, highlighting the adaptability of tumor–host interactions. Collectively, our findings demonstrate that miRNA-mediated regulatory networks not only drive NSCLC progression and inflammation but also contribute to systemic muscle wasting. These insights emphasize the need for novel therapeutic strategies, including RNA-based interventions, to overcome resistance, improve survival, and address the metabolic complications associated with NSCLC. Full article

Digestive system malignancies are a globally prevalent type of cancer that severely threatens human health. As pivotal intracellular transcriptional regulators, the forkhead box O (FOXO) protein family plays central roles in diverse physiological and pathological processes, including cell proliferation, apoptosis, and metabolism. Accumulating evidence has verified that FOXO factors exhibit dual functions as both tumor suppressors and oncoproteins. Notably, this functional duality displays a spatiotemporally specific switching pattern according to distinct stages of tumor progression and the physiological characteristics of different digestive system tumors, which poses substantial challenges for FOXO-targeted cancer therapy. Therefore, this review systematically summarizes the molecular mechanisms underlying the functional switching of FOXO in digestive system malignancies from the two dimensions of tumor progression stage and tumor-specific physiological properties, and elaborates the corresponding targeted therapeutic strategies. This work aims to provide a systematic theoretical reference for the precise intervention of digestive system tumors. Full article

Type 2 diabetes mellitus (T2DM) is frequently complicated by dyslipidemia, which accelerates insulin resistance and the progression of cardiovascular and hepatic diseases. While exercise intervention is a cornerstone of T2DM management, a systems-level understanding of its underlying molecular mechanisms remains incomplete. This article summarizes current evidence to propose that exercise functions as a signaling network regulator, concurrently modulating critical lipid metabolism-related signaling pathways: cyclic adenosine monophosphate (cAMP), phosphatidylinositol 3-kinase–protein kinase B (PI3K–AKT), forkhead box O (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways. We delineate how dysregulation of these signaling pathways contributes to lipid disorders in T2DM, highlighting their tissue-specific and often bidirectional roles. Subsequently, we detail the molecular adaptations induced by various exercise modalities—from aerobic training to high-intensity intervals—that restore homeostasis of this signaling network. By integrating these findings, we present a novel framework for precision exercise—defined as the tailoring of exercise modality, intensity, and volume based on an individual’s predominant signaling pathway disturbance, assessed via circulating or tissue-specific biomarkers. This framework advocates for future exercise prescriptions to be guided by molecular profiling alongside traditional physiological indicators. This mechanistic insight not only deepens our comprehension of exercise physiology but also paves the way for more effective, personalized strategies to combat T2DM and its metabolic complications. Full article

Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide, underscoring the need to better understand cardiovascular physiology. A key aspect involves identifying regulatory molecules that govern metabolic shifts. Forkhead box protein O1 (FoxO1) has emerged as a potential regulator; however, its role and underlying mechanisms remain unclear. This study investigated FoxO1 in metabolic adaptation using Wistar rats divided into age groups (fetal, postnatal day 1, postnatal day 7, adult) and treatment groups (control, hypoxia, FoxO1 inhibitor, combination). Hypoxia (12–14% O₂) and FoxO1 inhibitor (AS1842856, 10 mg/kgBW/day) were administered accordingly. Parameters assessed included hypoxia inducible factor 1 α (HIF-1α), FoxO1 mRNA and protein, glucose transporter type 1 (GLUT1), glucose transporter type 4 (GLUT4), cluster of differentiation 36 (CD36), hexokinase, pyruvate dehydrogenase kinase isoform 4 (PDK4), phosphoenolpyruvate carboxykinase (PEPCK), lactic acid, malonyl-CoA, carnitine palmitoyltransferase 1 (CPT1), citrate synthase, cytochrome c, and adenosine triphosphate (ATP). ATP production increased with age, associated with higher FoxO1 expression and metabolic shifts. Hypoxia in fetal hearts reduced HIF-1α and FoxO1. FoxO1 inhibition elevated glycolytic and oxidative markers. In conclusion, FoxO1 regulates glycolysis and lipid metabolism, offering insights into cardiac adaptation to hypoxia and potential therapeutic strategies. Full article

Aging is associated with complex physiological changes that influence drug pharmacokinetics, including alterations in mitochondrial function and gastrointestinal (GI) drug transporter activity. Mitochondrial dysfunction—characterized by reduced oxidative phosphorylation, mitochondrial DNA damage, and increased reactive oxygen species—is a hallmark of aging and may affect energy- and redox-dependent cellular processes in the gut. At the same time, aging can modulate the expression and function of key intestinal drug transporters from the ATP-binding cassette (ABC) and solute carrier (SLC) families, which play a central role in oral drug absorption and bioavailability. This review examines the molecular links between age-related mitochondrial dysfunction and regulation of GI drug transporters, with a focus on their pharmacokinetic consequences in older adults. We summarize evidence of mitochondrial decline in the aging intestine and discuss how mitochondrial signals—such as cellular energy status and oxidative stress—regulate transporter expression and activity via pathways including AMPK (AMP-Activated Protein Kinase), Sirtuin–FOXO (Forkhead box O transcription factors), Nrf2 (Nuclear factor erythroid 2-related factor 2), and NF-κB (Nuclear Factor kappa B). We highlight clinical examples of drugs showing age-related changes in bioavailability that may be attributable to transporter dysfunction. Finally, we discuss therapeutic implications for geriatric pharmacotherapy, including dose adjustment, management of transporter-mediated drug–drug interactions, and strategies aimed at preserving mitochondrial health. Full article

Objective: Accumulating evidence demonstrates that melatonin is involved in modulating granulosa cell function and follicular development. lncRNAs (long non-coding RNAs) and circRNAs (circular RNAs) have been reported to participate in multiple biological processes. This study aimed to explore the candidate circRNAs and lncRNAs related to molecular mechanisms when exploring the role of melatonin in regulating ovarian function. Methods: Bovine ovary granulosa cells were collected 48 h after treatment with melatonin at 10⁻⁷ M. The lncRNA and circRNA profiles of bovine granulosa cells were further explored using high-throughput sequencing in the absence/presence of melatonin. The differentially expressed lncRNAs and circRNAs were analyzed through the annotation information of source transcripts for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes). Results: We identified 99 differentially expressed lncRNAs and 28 differentially expressed circRNAs. Enrichment analysis of differentially expressed lncRNAs and circRNAs showed they were enriched in multiple pathways involved in development, apoptosis, and reproductive function, such as the mTOR (mammalian Target of Rapamycin) signaling pathway, FoxO (Forkhead box O) signaling pathway, MAPK (Mitogen-Activated Protein Kinase) signaling pathway, Hippo signaling pathway, TGF-beta (Transforming Growth Factor-β) signaling pathway, PI3K-Akt (Phosphatidylinositol 3-Kinase-Akt) signaling pathway, apoptosis, and Rap1 (Ras-related protein 1), most of which were mainly related to granulosa cell function and the crosstalk between granulosa cells and oocytes. The present analysis indicated the potential role of melatonin in granulosa cell function by regulating lncRNA and circRNA expression and, thus, mediating follicular development. An lncRNA/circRNA and miRNA regulatory network was also constructed to take their interactions into account. Conclusions: Our study offers details of lncRNA and circRNA expression in bovine granulosa cells and further provides insight into the potential role of melatonin in regulating reproduction by modulating lncRNA and circRNA expression. Full article

Background/Objectives: Cigarette smoking is a well-established risk factor for periodontal tissue damage caused by oxidative stress and increased proteolytic activity. Electronic cigarettes (e-cigarettes), marketed as less harmful alternatives, deliver nicotine and reactive compounds that may similarly disrupt periodontal health. However, their molecular effects on clinically healthy periodontal tissues remain unclear. This study aimed to compare oxidative stress-related and matrix-degradative biomarkers in the gingival crevicular fluid (GCF) of cigarette smokers (CS), e-cigarette (EC) users, and non-smokers (NS), and to examine the relationships among these markers. Methods: Sixty individuals, who were systemically and periodontally healthy (20 CS, 20 EC, and 20 NS), were examined. Clinical parameters, including probing depth (PD), clinical attachment level (CAL), plaque index (PI), and bleeding on probing (BOP), were recorded. GCF samples were analyzed for reactive oxygen species (ROS), matrix metalloproteinase-9 (MMP-9), and forkhead box protein O-1 (FOXO-1) using ELISA. Initial group comparisons were descriptive, followed by analysis of covariance (ANCOVA) to adjust for age; PI and PD were included as covariates in separate models. Correlations were assessed using Spearman’s analysis. Results: PD was significantly higher in both EC users and CS compared with NS (p = 0.022). MMP-9 levels were significantly higher in CS than in EC users and NS (p < 0.05), while FOXO-1 concentrations were significantly lower in CS compared with NS (p = 0.0227). ROS levels did not differ significantly among groups (p > 0.05). After adjustment for age, PI, or PD, group differences in MMP-9 and FOXO-1 remained statistically significant, whereas ROS levels remained comparable. FOXO-1 demonstrated positive correlations with ROS and MMP-9 within exposure groups; these associations were considered exploratory. Conclusions: In this cross-sectional study, CS and EC use were associated with altered matrix-regulatory biomarker profiles in clinically healthy periodontal tissues, independent of age and periodontal indices. Causal or temporal inferences cannot be drawn, and longitudinal studies are needed to clarify the long-term periodontal implications of these findings. Full article

Forkhead box protein O1 (Foxo1) is an insulin-suppressed transcription factor that governs multiple biological processes, including cell proliferation, apoptosis, autophagy, mitochondrial function, and energy metabolism. Over the past 25 years, Foxo1 has evolved from a liner insulin effector to a pleiotropic integrator of systemic metabolic stress during obesity and aging. Foxo1 integrates hormonal signals with energy balance and plays a central role in glucose and lipid metabolism, organ homeostasis, and immune responses. Given its pleiotropic functions, therapeutic targeting of Foxo1 pathway will require a nuanced, context-specific approach. Here, we reviewed key advances in Foxo1 studies over the past 25 years, including multi-hormonal control of Foxo1 activity, Foxo1-mediated inter-organ crosstalk, immune modulation, and contributions to aging-associated pathologies. Understanding the regulation of Foxo1 and its pleiotropic function across multiple tissues will advance insight into the pathogenesis of metabolic diseases and promote the translation potential of Foxo1 signaling manipulation for the treatment of metabolic disorders, including insulin resistance and type 2 diabetes. Full article

Neuroinflammation driven by microglial activation is a hallmark of Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial inflammation, yet strategies to modulate its expression remain limited. Safflower leaves, a vegetable rich in flavonoids—particularly luteolin—were previously shown to attenuate neuroinflammation, reduce oxidative stress, and ameliorate cognitive impairment in APP/PS1 mice. Here, we demonstrated that safflower leaves inhibit microglial inflammation and upregulate TREM2 in APP/PS1 mice. Luteolin, the major active flavonoid in safflower leaves, exerted anti-inflammatory effects in lipopolysaccharides (LPS)-activated microglia. Mechanistically, luteolin enhanced Trem2 transcription by activating forkhead box protein O3 (FOXO3), a novel transcriptional regulator of Trem2 identified through promoter analysis. FOXO3 binding to the Trem2 promoter was essential for this regulation, and luteolin further promoted FOXO3 nuclear translocation. Crucially, Trem2 knockdown attenuated luteolin’s anti-inflammatory effects, confirming TREM2 as a key mediator. Overall, our study reveals the FOXO3-TREM2 axis as a potential therapeutic target for neuroinflammation and highlights luteolin present in safflower leaves as a candidate dietary intervention for AD, providing new mechanistic insights into the anti-inflammatory activity of this natural antioxidant. Full article

Background: Diabetic nephropathy (DN) accelerates renal aging through chronic inflammation and metabolic dysregulation; however, the role of metformin in this process remains incompletely understood. This study investigated whether metformin attenuates diabetes-driven renal senescence through the modulation of the fatty acid-binding protein 4 (FABP4)/forkhead box protein O1 (FOXO1) axis and key immunometabolic enzymes. Methods: Thirty-two male Wistar rats were divided into healthy and diabetic groups and treated with either saline or metformin (200 mg/kg) for 10 weeks. Type 2 diabetes was induced by multiple low doses of streptozotocin (30 mg/kg, intraperitoneally) and high-fat diet. Renal function indices, lipid profile, inflammatory cytokines, succinate dehydrogenase (SDH), ATP-citrate lyase (ACLY), and senescence markers were measured, while FABP4 and FOXO1 expression, macrophage infiltration, and kidney histology were assessed using immunoassays and microscopy. Results: Metformin considerably reduced serum creatinine, urea, and blood urea nitrogen; normalized the lipid profile; suppressed interleukin (IL)-6 and tumor necrosis factor-α; and increased IL-10 levels. Additionally, it reversed DN-associated alterations in SDH and ACLY; downregulated FABP4, FOXO1, and P16^INK4a; decreased macrophage infiltration; promoted M2 polarization; and improved renal architecture. Conclusions: This study is the first to demonstrate that metformin mitigates diabetic renal senescence by simultaneously targeting the FABP4/FOXO1 axis and immunometabolic enzymes SDH and ACLY. These findings highlight the translational significance of metformin as a prototype for immunometabolic and immunosenescence-directed therapies in DN. Full article

Follicle selection is a pivotal process that determines which dominant prehierarchical follicle will enter the preovulatory hierarchy in the hen ovary and directly affects egg-laying productivity, in which granulosa cells (GCs) are characterized by active proliferation and significantly enhanced FSHR mRNA expression. Increasing evidence has shown that the PI3K/Akt signaling pathway and its important target and effector FOXO1, which promotes GC apoptosis, play crucial roles in ovarian follicular development in mammals. To investigate the molecular mechanism by which follicle-stimulating hormone (FSH)-mediated forkhead box O1 (FOXO1) participates in follicle selection, we treated granulosa cells from 6–8 mm prehierarchical follicles of chickens with FSH and leptomycin B (LMB). The results showed that under FSH and/or LMB treatment, the expression levels of FSHR, FOXO1, and its phosphorylated forms (p-FOXO1) at the predicted protein kinase B (PKB/Akt) phosphorylation sites Thr²⁴, Ser²⁴⁸, and Ser³¹¹ were differentially regulated. The subcellular localization of p-FOXO1 in hen ovarian GCs was determined by Western blotting and immunofluorescence staining (IF) analysis. And the expression of FOXO1 was significantly reduced, whereas the expression of p-FOXO1 corresponding to the PKB phosphorylation sites Ser²⁴⁸ and Ser³¹¹ was noticeably boosted in cultured GCs induced by FSH, accompanied by exclusion of FOXO1 from the nucleus to the cytoplasm. Subsequently, the effects of the PI3K/Akt signaling pathway on phosphorylation levels and nuclear exclusion of p-FOXO1 at the sites Ser²⁴⁸ and Ser³¹¹ were examined. The results indicate that the PI3K/Akt-dependent phosphorylation at these sites directly resulted in nuclear exclusion of FOXO1 in ovarian GCs, in which the Ser²⁴⁸ site is more essential than the Ser³¹¹ site. Subsequently, the FSH-induced acetylation of FOXO1 mediated by the cAMP/PKA pathway can enhance the phosphorylation level of FOXO1 at the Ser²⁴⁸ site. In summary, our findings demonstrate that FSH induces FOXO1 phosphorylation, nuclear exclusion, and functional inactivation by activating the PI3K/Akt signaling pathway. Moreover, during follicular development and selection, FOXO1 acts as a pivotal mediator linking the PI3K/Akt and P62/Keap1/Nrf2 signaling pathways to regulate granulosa cell proliferation and apoptosis, thereby exerting a central regulatory role. Full article