Search Results (3,169)

Both RIT1 and RIT2 are members of the RAS superfamily of small GTPases, which regulate various cellular processes. RIT1 is widely expressed, whereas RIT2 is primarily found in neuronal tissues. Dysregulation of these proteins has been associated with several human diseases, including Noonan syndrome, cancer, Parkinson’s disease, autism, and schizophrenia. Although RIT1 and RIT2 are often compared to classical RAS proteins, they exhibit distinct regulatory and biochemical properties. Here, we demonstrate that RIT1 differs from classical RAS in GTPase cycling. Unlike classical RAS proteins, RIT1 did not respond to SOS1-mediated nucleotide exchange or p120GAP-stimulated GTP hydrolysis under cell-free conditions. These results imply that RIT1 may depend on regulatory mechanisms that differ from those of classical RAS proteins. However, the relevant physiological regulators remain unknown. Disease-associated RIT1 mutations cluster around the P-loop and Switch II regions. In this transient overexpression screening system, however, these mutations had only a modest effect on the canonical MAPK, PI3K/AKT, and JNK signaling pathways in HEK293T overexpression experiments. This suggests the existence of additional context-specific effectors and regulatory factors. We demonstrate that RIT1 and RIT2 interact with membrane lipids via a basic C-terminal extension. The KRLK-containing region contributes to the binding of phosphatidylserine and phosphoinositides. Charge-reversal mutations disrupt lipid interactions and liposome binding, supporting the functional importance of this region. In a reconstituted liposome system, galectin-3 and LZTR1, but not galectin-1, reduced the interaction of GDP-loaded RIT1 and RIT2 with liposomes. These results suggest that accessory proteins may influence RIT membrane interactions. However, their cellular relevance requires further validation. Together, our findings provide biochemical insights into RIT GTPase regulation and its interactions with membrane lipids under cell-free conditions. Full article

Type 2 diabetes (T2D) is a metabolic syndrome frequently associated with obesity and endoplasmic reticulum stress-mediated inflammation, which can trigger the unfolded protein response (UPR), impair insulin signaling, and promote apoptosis. To identify potential natural therapeutic candidates, this study investigated the mechanisms of action of 14 compounds from Uncaria tomentosa (UT), a medicinal plant from the Amazon rainforest, using in silico modeling. The study focused on the UPR, TRAF2/JNK pro-inflammatory signaling pathway, and insulin signaling pathways, which play key roles in T2D. Some of the UT compounds were docked against several human proteins involved in these pathways, and molecular dynamics simulations confirmed stable interactions between the target proteins (PERK, TRAF2, JNK, TNF-α, IRS-1, PI3K, AKT, GSK3β, and PPARγ) and four of the UT compounds, 5-Carboxystrictosidine, Cinchonain, Epicatechin and Mitraphylline. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties analyses were conducted to predict the four compounds, revealing suitable pharmacokinetic properties. These findings suggest that specific UT compounds may be used in experimental tests to whether investigate their therapeutic potential in managing T2D by modulating signaling pathways related to the conditions UPR, inflammation, and insulin resistance. Full article

Fractional ionizing radiation (FIR) is a standard cancer therapy but often induces severe central nervous system complications, including cognitive decline and physiological dysfunction. While natural flavonoids hold therapeutic promise for radiation-induced brain injury (RIBI), optimizing their combinations and elucidating the underlying molecular pathways remain challenging. Methods: To develop a precise therapeutic strategy, we first integrated network pharmacology and UHPLC-Q-Orbitrap MS/MS analysis to identify three highly effective flavonoid monomers from a radioprotective botanical extract. Subsequently, an in vivo anti-inflammatory screening was conducted to determine the optimal combinatorial ratio, designated as the ternary formulation QLI. The neuroprotective efficacy of QLI was then systematically evaluated in a mouse model of fractional RIBI (cumulative dose of 12 Gy) through behavioral assessments, hematopoietic profiling, and neurotransmitter analyses. Transcriptomic alterations were explored via RNA-sequencing (RNA-seq) and validated by molecular docking, RT-qPCR, and Western blotting. Results: Pharmacological and mass spectrometry analyses identified Quercetin, Luteolin, and Isorhamnetin-3-O-glucoside as the core bioactive monomers. Quantitative synergistic screening established the optimal QLI formulation at a mass ratio of 2:1:1. In vivo, FIR exposure induced severe spatial memory deficits, disrupted neurotransmitter homeostasis, and caused hematopoietic decline. Administration of QLI successfully reversed these physiological and cognitive impairments. Transcriptomic profiling revealed that QLI globally reprogrammed aberrant gene expression, specifically normalizing signaling networks related to the PI3K–Akt pathway, apoptosis, and neuroactive ligand–receptor interactions. Multidimensional validation confirmed that QLI mitigated neuroinflammation, suppressed astrocyte hyperactivation (GFAP), and preserved synaptic plasticity by preventing the pathological accumulation of SynGAP and autophagic stress (Beclin-1). Conclusions: The rationally designed ternary flavonoid formulation (QLI) provides potent neuroprotection against fractional RIBI. By resolving neuroinflammation, alleviating synaptic plasticity suppression, and normalizing stress-induced transcriptomic disruptions, QLI represents a promising multi-target experimental formulation with the potential to mitigate radiotherapy-associated neurological side effects. Full article

Cirsium japonicum Fisch. ex DC. has long been used in traditional East Asian medicine and has attracted increasing attention because of its diverse pharmacological activities, including antioxidant, anti-inflammatory, antifibrotic, metabolic regulatory, and anticancer effects. Although numerous studies have investigated its phytochemical composition and biological activities, current evidence has largely been organized according to individual compounds or disease categories, providing limited insight into the shared molecular mechanisms underlying its pleiotropic actions. In this review, we critically re-evaluate the molecular pharmacology of C. japonicum using an evidence-oriented framework that distinguishes experimentally supported mechanisms from pharmacological associations and emerging hypotheses. Rather than accepting changes in signaling proteins or downstream biomarkers as sufficient evidence of mechanism, we assess the strength of evidence based on reproducibility, pathway-specific interventions, genetic or pharmacological validation, and direct target engagement. Current evidence indicates that nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant responses and nuclear factor kappa B (NF-κB)-associated inflammatory responses represent the most consistently observed pathway associations, although direct molecular targets and causal pathway dependency remain insufficiently established. Evidence for AMPK/PI3K-Akt-associated metabolic regulation and TGF-β/Smad-associated antifibrotic responses is comparatively more limited. In contrast, modulation of apoptosis and autophagy is currently supported primarily by indirect or context-dependent observations. We further discuss how multiple phytochemicals converge on interconnected signaling networks regulating oxidative stress, inflammation, metabolism, tissue remodeling, and cell fate, thereby providing a systems-level explanation for the broad therapeutic potential of C. japonicum. Finally, we highlight the need for standardized phytochemical characterization, rigorous target validation, multi-omics integration, and artificial intelligence-assisted systems biology to establish causal molecular mechanisms and accelerate the translational development of evidence-based phytopharmaceuticals. Full article

Background: Neuropathic pain (NP) is a debilitating chronic condition driven by maladaptive neuroimmune interactions in the spinal cord, with microglia playing a central pathological role. Electroacupuncture (EA) has shown analgesic effects in clinical and preclinical studies, but the microglia-centered mechanisms underlying these effects remain incompletely integrated. This review aims to provide a comprehensive mechanistic synthesis of how EA modulates microglia-associated neuroinflammatory pathways in neuropathic pain. Methods: This systematic search-narrative review used systematic search and screening procedures to identify English-language animal studies published between 2015 and 2025 in PubMed, CINAHL, Web of Science, and Cochrane Library. Twenty-six animal studies investigating EA effects on microglia-associated signaling pathways in neuropathic pain models met the inclusion criteria. Because of substantial heterogeneity in neuropathic pain models, EA parameters, molecular endpoints, and behavioral outcomes, findings were synthesized narratively, and no meta-analysis was performed. Results: The reviewed evidence revealed four convergent mechanistic categories through which EA modulates microglial activity: (1) attenuation of purinergic microglial activation via downregulation of IRF8, P2X4R, P2X7R; (2) suppression of innate immune sensing and inflammasome pathways, including TLR4/MyD88/NF-κB and NLRP3 signaling; (3) inhibition of downstream inflammatory amplification through p38 MAPK, PI3K/AKT, and COX-2 pathways; and (4) promotion of pro-resolution mechanisms involving IL-10/β-endorphin, PD-L1, GRK2/TREM2/DAP12, α7nAChR, GLP-1R, and GABAergic signaling. Conclusions: The available preclinical evidence suggests that EA modulates multiple microglia-associated pathways, attenuating inflammatory signaling while enhancing selected pro-resolution mechanisms. These findings provide a mechanistic framework for understanding EA-induced analgesia in neuropathic pain and highlight microglial signaling networks as important targets for future experimental and translational investigation. Full article

Background/Objectives: Hypoxia is a major contributor to the development of retinal diseases by promoting metabolic adaptation and pathological angiogenesis through hypoxia-inducible factor (HIF) signaling. HIF-prolyl hydroxylase inhibitors (HIF-PHIs), which stabilize HIF under normoxic conditions, are widely used to treat anemia associated with chronic kidney disease. However, it remains unclear whether pharmacological HIF stabilization fully reproduces the cellular responses induced by physiological hypoxia. Methods: In this study, ARPE-19 cells were exposed to either physiological hypoxia or HIF-PHI treatment and analyzed using RNA sequencing, pathway enrichment, and pharmacological inhibition of PI3K/Akt, mTOR, and HIF-related signaling pathways. Results: Both treatments elicited a common transcriptional response marked by the induction of glycolytic and hypoxia-responsive genes together with increased vascular endothelial growth factor a VEGFA expression. Despite these similarities, only a small number of genes differed between the two conditions, suggesting that physiological hypoxia activates additional regulatory mechanisms beyond HIF stabilization alone. Rapamycin inhibited VEGFA production only under physiological hypoxia, further supporting mechanistic differences between the two models. Functionally, conditioned media from hypoxic ARPE-19 cells promoted endothelial tube formation, which was significantly reduced by pathway inhibition. Conclusions: Collectively, these findings show that HIF-PHIs reproduce many, but not all, aspects of the physiological hypoxic response in RPE cells. Full article

Background/Objective: Traditionally derived from the dried leaves of Microcos paniculata L., Microctis folium (M. folium) has been employed to manage various inflammatory and metabolic conditions. Despite its reported hypolipidemic potential, the active constituents contributing to this effect and their molecular mechanisms of action remain to be determined. Therefore, this study aimed to systematically identify the active hypolipidemic constituents of M. folium and elucidate their mechanisms of action through an integrated strategy combining chemical profiling, pharmacokinetic screening, network pharmacology, and experimental validation. Methods: UPLC fingerprint and UPLC-QQQ-MS/MS were employed to characterize and quantify the chemical constituents of M. folium. Pharmacokinetic analysis was conducted to identify systemically absorbed compounds. Network pharmacology was applied to predict potential targets and signaling pathways. The lipid-lowering effects were subsequently validated in vitro using an oleic acid/palmitic acid (OA/PA)-induced lipid accumulation model in HepG2 cells and in vivo in a Triton WR-1339-induced hyperlipidemia mouse model. Results: UPLC fingerprint analysis identified 15 common peaks among 21 batches of M. folium, with similarity values ranging from 0.885 to 0.990, indicating good chemical consistency. Eighteen representative compounds were quantified, among which flavone C-glycosides and phenolic acids were predominant. Pharmacokinetic results demonstrated that multiple M. folium’s constituents were absorbed into systemic circulation. Network pharmacology analysis identified 73 potential targets related to hyperlipidemia and highlighted the PI3K-Akt signaling pathway as a key regulatory pathway. In vitro experiments showed that M. folium’s compounds significantly reduced intracellular lipid accumulation and oxidative stress in OA/PA-induced HepG2 cells. Furthermore, in vivo studies demonstrated that vitexin, ferulic acid, isoferulic acid, and N-trans-feruloyltyramine significantly reduced serum and hepatic lipid levels, including TC, TG, and LDL-c, alleviated hepatic steatosis, and improved liver injury and oxidative stress markers in Triton WR-1339-induced hyperlipidemic mice. Conclusions: M. folium exerts significant lipid-lowering effects through multi-component and multi-target mechanisms involving regulation of lipid metabolism and oxidative stress, partly mediated by activation of the PI3K-Akt signaling pathway. These findings provide a scientific basis for the development of M. folium’s natural agents for the treatment of hyperlipidemia. Full article

Background: Low maternal folate status is associated with placental dysfunction and adverse pregnancy outcomes; however, the mechanisms linking reduced folate availability to altered placental function remain incompletely understood. We investigated whether folate deficiency directly alters trophoblast function and microRNA (miRNA) expression, and whether folate-responsive miRNAs mediate these functional changes. Methods and Results: Human placental villous explants, BeWo choriocarcinoma cells, and primary human cytotrophoblasts were cultured under physiological or folate-deficient conditions to assess the direct impact of reduced folate availability. Although intracellular folate depletion was achieved in all models, only primary cytotrophoblasts reproduced functional changes consistent with those observed in placentas from folate-deficient pregnancies, exhibiting increased apoptosis and reduced system A amino acid transport. Of sixteen miRNAs previously associated with low maternal folate status, miR-30e-3p and miR-34b-5p were significantly reduced in trophoblast following folate depletion. Targeted inhibition of either miRNA did not alter apoptosis or system A activity. Pathway analysis of differentially expressed genes following miRNA inhibition identified processes related to cytoskeletal organisation, cell adhesion, PI3K/AKT and MAPK signalling. Conclusions: Folate deficiency directly impairs trophoblast survival, amino acid transport, and miRNA expression in primary trophoblasts. Our findings demonstrate that only a subset of folate-associated placental miRNAs respond directly to folate depletion and that inhibition of individual folate-responsive miRNAs is insufficient to reproduce the trophoblast phenotype. These results indicate that trophoblast adaptation to reduced folate availability is likely mediated through coordinated nutrient-sensitive regulatory networks rather than individual miRNAs acting in isolation. Full article

Exposure to ambient particulate matter (PM) has been linked to renal dysfunction, particularly in diabetic populations, but the underlying mechanisms remain unclear. We performed bidirectional Mendelian randomization to assess causal relationships between PM exposure and estimated glomerular filtration rate (eGFR), integrated transcriptomic datasets to identify PM-related genes overlapping with diabetic kidney disease (DKD) differentially expressed genes, and applied machine learning approaches to select key feature genes and construct diagnostic models. Single-cell and spatial transcriptomic analyses were used to characterize cell-type and region-specific expression patterns, while in silico knockout analysis explored potential functional associations. PM2.5–10 exposure was causally associated with decreased eGFR, particularly among individuals with diabetes, with no evidence of reverse causality. Transcriptomic integration identified 168 shared PM-DKD genes enriched in inflammatory, immune, and metabolic pathways, including AGE-RAGE, IL-17, TNF, and PI3K-Akt signaling. Seven feature genes (AVPI1, DUSP1, FOSB, JUNB, PDK2, TPPP3, and VIM) showed good diagnostic performance across training and external validation cohorts, and machine learning models and nomogram analyses demonstrated consistent predictive performance. Single-cell and spatial transcriptomic analyses revealed distinct cell-type and region-specific expression patterns, with VIM enriched in interstitial and fibrotic regions, TPPP3 mainly detected in podocytes, and other genes distributed across tubular or immune cell populations. In silico knockout analysis suggested potential associations of these genes with mitochondrial metabolism, oxidative stress, tubular function, and inflammatory processes. Database-based therapeutic exploration identified VIM as a potential candidate target, with sanguinarine showing favorable predicted binding affinity. Collectively, these findings suggest that PM2.5–10 exposure may contribute to DKD susceptibility through inflammatory, metabolic, and oxidative stress-related mechanisms, and provide candidate molecular markers for further investigation. Full article

Wound healing is a dynamic and highly coordinated process that involves inflammation, cell proliferation, angiogenesis, re-epithelialization, extracellular matrix remodeling, and tissue maturation. The altered expression of important signaling pathways, such as transforming growth factor-β (TGF-β)/Smad, nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin, may be responsible for slower wound healing, chronic inflammation, excessive fibrosis, and impaired tissue regeneration. Multifunctional nanomaterials are a promising strategy for tuning these highly coordinated processes due to their tunable physicochemical properties, high surface area, and the ability to deliver cargo, as well as the integration of antimicrobial, antioxidant, anti-inflammatory, and pro-angiogenic properties. The aim of current review is to summarize the potential of multifunctional nanomaterials to promote wound healing, with a focus on mechanisms of action and modulation of key cellular signaling pathways. A systematic review of the literature was conducted using PubMed, Scopus, Web of Science, and Google Scholar, searching for publications from 1996 to June 2026, and representative experimental, mechanistic, preclinical, and translational studies were critically evaluated. In this review, the authors discuss the role of nanomaterial properties, therapeutic payload, molecular targets, modulation of cellular signaling pathways, and regenerative effects. These platforms have been shown in in vitro and animal studies to influence inflammatory signaling, oxidative stress, angiogenesis, collagen remodeling, re-epithelialization, cellular proliferation, and migration. However, the modulation of these pathways are dose-responsive, time-dependent, and cell- and wound-stage-specific. Despite the promising therapeutic potential of nanomaterial-based wound care strategies, the available evidence remains predominantly preclinical, with relatively limited clinical data supporting their use in humans. Concerns regarding long-term toxicity, biodistribution, batch-to-batch reproducibility, sterilization, scalable manufacturing, regulatory approval, and commercial feasibility further challenge translation into clinical practice. Multifunctional nanomaterials may offer a promising approach for pathway-specific and multimodal wound management; however, comprehensive mechanistic studies, long-term safety and biodistribution assessments, and well-designed clinically relevant investigations are required to establish their efficacy, safety, and true translational potential. Full article

Background/Objectives: Cerebral ischemia–reperfusion injury (CIRI) poses therapeutic challenges because of oxidative stress, blood–brain barrier disruption, and neuronal apoptosis, limiting current treatments. Paeoniflorin (PF) from Paeonia lactiflora has neuroprotective potential, but its multi-target mechanisms remain unclear. This study investigated the role and mechanisms of PF in CIRI, focusing on neuron–endothelial crosstalk. Methods: Oxygen–glucose deprivation/reoxygenation (OGD/R) models were established using SH-SY5Y (human neuroblastoma) and HCMEC/D3 cells (human cerebral microvascular endothelial). Network pharmacology was used to predict potential PF targets and pathways. RNA sequencing, molecular docking, and molecular dynamics simulation were performed to screen and evaluate PF binding characteristics with key targets, and MTT, flow cytometry, Western blotting, and co-cultures were employed to detect paracrine interactions. Results: Network pharmacology and transcriptomics identified VEGF/PI3K-AKT/mTOR pathway enrichment. Molecular docking confirmed stable PF binding to VEGF-A (−8.4 kcal/mol), AKT (−5.5 kcal/mol), and mTOR (−9.6 kcal/mol). PF (10–80 μM) showed no cytotoxicity and reduced OGD/R injury in a concentration-dependent manner (maximal at 40 μM). PF activated VEGF/PI3K-AKT/mTOR signaling, reducing apoptosis by 57% (SH-SY5Y) and 33% (HCMEC/D3); PI3K inhibitor LY294002 abolished these effects. PF-treated HCMEC/D3-conditioned media enhanced OGD/R neuronal viability, verifying paracrine crosstalk. Conclusions: PF alleviated CIRI by directly protecting neurons and indirectly modulating neuron–endothelial crosstalk through VEGF/PI3K-AKT/mTOR activation, supporting its multi-target therapeutic potential. Full article

Coronary artery disease is a leading cause of morbidity and mortality in modern medicine. In contrast, surgical myocardial revascularization via coronary artery bypass grafting (CABG) remains the gold standard of treatment for complex multivessel disease. The great saphenous vein remains the most frequently used conduit due to its availability and technical simplicity, but its long-term patency is significantly inferior to that of arterial grafts. The primary pathological process responsible for vein graft failure is intimal hyperplasia, which represents a complex response of the vascular wall to surgical trauma, vein arterialization, inflammation, and hemodynamic stress. This process is characterized by endothelial dysfunction, inflammatory cell activation, proliferation and migration of vascular smooth muscle cells, and extracellular matrix remodeling. Underpinning these alterations are numerous molecular pathways, including NF-κB, MAPK, PI3K/Akt, TGF-β, and mTOR signaling, as well as substantial contributions from oxidative stress, cytokines, growth factors, and microRNAs. Contemporary research indicates that the phenotypic transformation of vascular smooth muscle cells constitutes the central event in the development of intimal hyperplasia. Understanding the cellular and molecular mechanisms underlying this disease’s onset enables the development of novel therapeutic strategies to preserve long-term graft patency. This review paper aims to provide a systematic overview of current knowledge regarding the molecular and cellular mechanisms of intimal hyperplasia development in vein grafts following CABG. Full article

Cancer remains a highly complex and heterogeneous disease, causing major morbidity and mortality worldwide despite advances in diagnosis and treatment. The hallmarks of cancer enlighten the biological mechanisms supporting tumourigenesis and malignant evolution, while helping to identify potential therapeutic targets. Medical cannabis has mostly been used in oncology for supportive care, but increasing preclinical evidence suggests interference with cancer-related signalling pathways. This narrative review summarizes the current evidence on cannabinoids, in particular the phytocannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), framing their prospective anticancer effects in the hallmarks of cancer. Preclinical studies imply that CBD exerts antiproliferative effects by modulating oncogenic signalling pathways, including EGFR, PI3K/AKT, RAS/RAF/ERK, mTOR and Wnt/β-catenin, while also influencing tumour suppressor pathways involving p53, p21 and p27, causing cell cycle arrest. CBD has additionally been shown to promote programmed cell death via mitochondrial dysfunction and autophagy, altering cancer metabolism as well. Furthermore, CBD has shown anti-invasive and antiangiogenic properties and also appears to modulate immune responses and interactions with the tumour microenvironment, including emerging links with the microbiome. Overall, cannabinoids exhibit biologically plausible antitumour activity across multiple cancer hallmarks and may present promising candidates for combination therapeutic strategies. Nonetheless, the current evidence remains predominantly preclinical, and robust translational studies and clinical trials are needed to clarify their pharmacokinetic and pharmacodynamic profiles, determine their clinical efficacy and safety while assessing their potential integration into multimodal cancer treatment. Full article

Hair follicle stem cells (HFSCs) are critical for hair follicle (HF) morphogenesis and cyclic hair regeneration. Periostin (POSTN), an extracellular matrix protein involved in tissue development and skin cell regulation, remains poorly characterized in HFSCs. In this study, we constructed CRISPR/Cas9 vectors targeting POSTN and validated their editing efficiency in primary HFSCs. POSTN editing significantly suppressed cell proliferation and promoted apoptosis. Transcriptomic analysis identified 988 differentially expressed genes (DEGs) enriched in immune responses and MAPK, PI3K–Akt, and cAMP pathways. Metabolomic analysis revealed 98 differential metabolites (DMs) associated with nucleotide metabolism and FoxO, AMPK, and cAMP pathways. Integrated multi-omics analysis showed extensive correlations between DEGs and DMs, and highlighted the cAMP pathway as the core regulatory axis. Western blot (WB) validation confirmed that POSTN editing reduced PKA and CREB phosphorylation, indicating inhibition of the cAMP/PKA/CREB signaling. These findings demonstrate that POSTN regulates HFSCs’ proliferation and apoptosis partially via the cAMP/PKA/CREB pathway, providing novel insights into the functional regulation of HFSCs. Full article

Background: High-altitude hypobaric hypoxia (HH) is a major environmental stressor that impairs cognitive function, yet effective and widely available therapeutics remain limited. Although Rhodiola rosea has shown neuroprotective effects, its resource scarcity restricts large-scale application. Cistanche tubulosa (Schrenk) Wight, a traditional Chinese functional food, has been increasingly used in health supplements due to its anti-fatigue, anti-dementia, and memory-enhancing properties, suggesting potential benefits against hypoxia-induced cognitive impairment. Objective: This study aimed to investigate the effects of C. tubulosa ethanol extract (CTE) on hippocampal tissue and gut microbiota upon chronic HH exposure using SPF male Sprague–Dawley (SD) rats. Methods: A total of 60 male SD rats were randomly assigned to six experimental groups (n = 10 per group): normoxic control, untreated HH model, positive control (R. rosea), and low-, medium-, high-dose CTE treatment groups. Behavioral tests (Morris water maze), hippocampal histopathology, serum and hippocampal oxidative stress markers (SOD, GSH-Px, MDA), expression of PI3K/Akt/mTOR-HIF-1α signaling pathway proteins (by immunohistochemistry), and gut microbiota composition (by 16S rRNA sequencing) were evaluated. Results: The results demonstrated that CTE significantly improved cognitive function, enhanced SOD and GSH activities, and reduced MDA levels in both hippocampus and serum. CTE also modulated the expression of PI3K/Akt/mTOR-HIF-1α pathway proteins in the hippocampus. Furthermore, CTE altered gut microbial diversity and abundance, increasing the proportion of beneficial bacteria, which may further influence hippocampal function via the gut–brain axis. Conclusion: These findings provide scientific evidence for the application of C. tubulosa as a potential health supplement for high-altitude adaptation and lay a foundation for subsequent research. Full article