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PubMed2026

Impact of NR4A3 on wound healing in chronic venous ulcers and its association with the PI3K/Akt signaling pathway.

BACKGROUND: To investigate the role of NR4A3 in chronic venous ulcer (VU) wound healing and to explore its potential regulatory mechanism involving the PI3K/Akt pathway. METHODS: Differential expression and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the GSE174661 dataset. DEGs were filtered by |log2FC| > 1 and adjusted P < 0.05, with KEGG significance set at P < 0.05. NR4A3 was identified as the core gene. NR4A3 knockdown and overexpression were established in HaCaT cells to evaluate proliferation, migration, and inflammatory cytokines. TNF-α was used to mimic the inflammatory microenvironment. Western blotting assessed phosphorylation of GSK3β, mTOR, PI3K, and Akt. PI3K/Akt agonist 740Y-P and inhibitor LY294002 were used in rescue experiments. RESULTS: Bioinformatic analysis revealed that NR4A3 expression was markedly downregulated in chronic venous ulcer (VU) tissues relative to normal skin and ordinary acute wound tissues. Differentially expressed genes were significantly enriched in the PI3K/Akt signaling pathway. TNF-α stimulation significantly upregulated NR4A3 expression and increased phosphorylation of GSK3β and mTOR in HaCaT cells. In cultured HaCaT keratinocytes, NR4A3 knockdown suppressed cell proliferation and invasion, enhanced cell migration, and elevated the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8, CXCL5), accompanied by reduced phosphorylation of PI3K and Akt. Conversely, NR4A3 overexpression promoted cell proliferation and invasion, restrained migration, and dampened inflammatory responses, while increasing PI3K/Akt phosphorylation. Treatment with the PI3K/Akt agonist 740Y-P partially rescued the impaired proliferation, aberrant migration, and excessive inflammation caused by NR4A3 silencing, whereas PI3K/Akt inhibitor LY294002 aggravated pathway suppression. These findings suggest that NR4A3-associated changes in keratinocyte functions and inflammatory reactions are functionally linked to PI3K/Akt pathway activity, and inflammatory stimulation activates GSK3β/mTOR signaling accompanied by compensatory NR4A3 upregulation. CONCLUSION: These findings suggest that NR4A3 is associated with keratinocyte behavior and inflammatory responses via the PI3K/Akt pathway, potentially affecting chronic VU progression and healing. Reduced NR4A3 may impair wound repair through inflammation and abnormal cell migration, while TNF-α induces compensatory NR4A3 elevation.

NR4A3↗

PubMed2025

Growth Hormone Alleviates Atherosclerosis Through Regulating the Activity of PI3K/AKT Pathway: Insights From Single-Cell Sequence and Mechanism Exploration.

PURPOSE: This research sought to investigate the impact and underlying mechanisms of growth hormone (GH) on atherosclerosis (AS) based on the analysis of single-cell RNA sequencing (scRNA-seq) data. METHODS: We analyzed the impact of GH on arterial vascular smooth muscle cells (VSMCs) by utilizing scRNA-seq data obtained from both atherosclerotic and healthy vascular tissues in mice. AS was induced in C57BL/6 and ApoE-/- mice through hypophysectomy performed via the parapharyngeal approach, followed by a high-fat diet (HFD), resulting in the C57-Hx and ApoE-/--Hx models. AS was evaluated by measuring arterial lipid deposition, plaque progression, collagen loss, vascular inflammation, and oxidative stress. Serum metabolite alterations were assessed using liquid chromatography-mass spectrometry (LC-MS). RNA sequencing was employed to examine the underlying mechanisms of GH in the context of AS treatment, with findings further confirmed through western blot analysis. In vitro experiments involved treating VSMCs with oxidized low-density lipoprotein (ox-LDL) to simulate atherosclerotic injury. The formation of foam cells was evaluated by measuring lipid accumulation, inflammatory responses, apoptosis, and the expression levels of foam cell-related markers. Finally, the PI3K/AKT inhibitor LY294002 confirmed that GH alleviates AS via the PI3K/AKT signaling pathway. RESULTS: scRNA-seq data analysis showed that growth hormone signaling was reduced in VSMCs of atherosclerotic arteries. HFD led to elevated levels of serum total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), accompanied by increased lipid deposition, inflammatory responses, and oxidative stress. In contrast, high-density lipoprotein cholesterol (HDL-C) and insulin-like growth factor 1 (IGF-1) levels were lower in C57-Hx mice. GH treatment improved HFD-induced AS in ApoE-/--Hx mice. LC-MS analysis revealed that GH altered lipid metabolism in serum samples from C57-sham, C57-Hx, ApoE-/--Hx, and ApoE-/--Hx-GH(3) mice. GH maintained lipid balance by increasing 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), PE-NMe2(18:1(9z)/18:1(9z)) (DMPE), and 4-chloro-2-nitrobenzylalcohol levels and decreasing 1-heptadecanoyl-sn-glycerol-3-phosphocholine. RNA sequencing showed significant gene expression differences in the aortas of C57-sham and C57-Hx mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that GH inhibited the progression of AS by modulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, a finding that was validated through western blotting. Further in vitro studies demonstrated that GH exerted protective effects on VSMCs against ox-LDL-induced damage through activation of the PI3K/AKT pathway, as evidenced by experiments using the specific PI3K inhibitor LY294002. CONCLUSION: GH alleviates the development of AS through the activation of the PI3K/AKT pathway. The findings of this research emphasize the therapeutic potential of GH in inhibiting AS and highlight the importance of the PI3K/AKT pathway as a promising target for clinical intervention.

PI3K/AKT signaling pathway↗

PubMed2026

POFUT1 Serves as an Independent Prognostic Factor and Therapeutic Target by Activating the PI3K/AKT Pathway in Glioma.

OBJECTIVE: Protein O-fucosyltransferase 1 (POFUT1) has been implicated in several malignancies, but its functional and prognostic significance in glioma remains insufficiently defined. This study evaluated whether POFUT1 expression is associated with glioma progression, patient outcome, and PI3K/AKT pathway activity. METHODS: Public glioma transcriptome datasets from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) were analyzed and compared with clinical samples collected from 123 glioma patients. POFUT1 protein levels in clinical specimens were determined by immunohistochemical staining, and its association with patient outcome was analyzed using survival curves. In vitro, glioma cell growth, motility, and invasiveness were examined using MTT and Transwell assays. The effect of POFUT1 on tumor formation was further tested in a subcutaneous xenograft model. RNA sequencing, KEGG pathway enrichment, and pharmacological inhibition were then used to explore the mechanism linking POFUT1 to PI3K/AKT signaling. RESULTS: POFUT1 expression was higher in glioma than in normal brain tissue and increased with tumor grade. Patients with high POFUT1 levels had shorter overall survival, and multivariate Cox analyses supported POFUT1 as an independent prognostic indicator. Incorporating POFUT1 into a nomogram improved prediction of 1-, 3-, and 5-year survival. Functionally, POFUT1 knockdown reduced glioma cell growth, motility, invasion, and xenograft expansion, whereas POFUT1 overexpression produced the opposite phenotype. Transcriptomic and protein analyses indicated that POFUT1 enhanced PI3K/AKT signaling. The PI3K inhibitor LY294002 weakened the tumor-promoting effects caused by POFUT1 overexpression. CONCLUSION: POFUT1 as a key driver of glioma malignancy, predominantly through activating the PI3K-AKT signaling pathway. These findings highlight POFUT1 as a promising novel therapeutic target for aggressive glioma.

Glioma↗

PubMed2026

CCNA2 orchestrates the PI3K/AKT signaling axis to propel prostate cancer metastasis.

BACKGROUND: Prostate cancer (PCa) remains one of the most common malignancies in men, posing a persistent global burden in terms of both public health and socioeconomic costs. Although early detection is essential for improving patient outcomes, existing clinical tools, including prostate-specific antigen (PSA) screening, digital rectal examination, and transrectal ultrasound-guided biopsy, are hampered by suboptimal specificity and positive predictive value, resulting in frequent overdiagnosis and overtreatment of indolent lesions while missing a subset of aggressive tumors at an early stage. In this context, the rapid advancement of high-throughput omics technologies, coupled with sophisticated machine learning (ML) algorithms, provides a powerful computational framework to dissect high-dimensional genomic data, uncover latent gene expression signatures, and identify candidate biomarkers with superior discriminative performance over conventional clinicopathological parameters. Therefore, in this study, we sought to screen for crucial ML-based biomarkers associated with PCa, with a particular focus on systematically assessing the diagnostic and prognostic value of CCNA2. Leveraging large-scale transcriptomic cohorts from public repositories, we employed an ensemble of ML approaches to prioritize candidate genes and subsequently evaluated the diagnostic performance of CCNA2 through receiver operating characteristic curve analysis, as well as its prognostic utility via Kaplan-Meier survival estimation and multivariate Cox proportional hazards modeling. Our findings are anticipated to elucidate the molecular landscape of PCa and offer a promising biomarker candidate for early detection and risk stratification. METHODS: This study integrated single-cell RNA sequencing, bulk transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories, immunofluorescence, and multiple ML algorithms with in vitro functional assays to evaluate CCNA2 expression, clinical relevance, and biological behavior in PCa. RESULTS: CCNA2 was linked to metastasis and poor prognosis. High CCNA2 expression significantly correlated with adverse survival outcomes, and knockdown of CCNA2 suppressed proliferation, migration, and invasion in PCa cell lines. Mechanistically, CCNA2 modulated the PI3K/AKT signaling pathway. An ML-based diagnostic model incorporating CCNA2 demonstrated high predictive accuracy across multiple validation cohorts. CONCLUSIONS: CCNA2 serves as a promising prognostic biomarker and therapeutic target in prostate adenocarcinoma, driving tumor progression potentially via the PI3K/AKT axis.

CCNA2↗

PubMed2025

Amylin inhibits gastric cancer progression by targeting CCN1 and affecting the PI3K/AKT signalling pathway.

METHODS: This study used a combination of in vitro and in vivo experiments to investigate the role of amylin in the progression of GC. The expression of amylin in GC and its clinical correlation were evaluated using 38 pairs of GC and healthy human clinical samples. In vitro studies, human GC cell lines were treated with amylin to evaluate the effects of amylin on the proliferation, apoptosis and migration of GC cells. In in vivo studies, xenograft mouse models were established by subcutaneous injection of GC cells into nude mice, followed by treatment with amylin to assess tumor growth. Finally, Next-Generation Sequencing Technology (RNA-seq) was used to explore the potential mechanism of amylin on GC. RESULTS: We found that amylin expression was reduced in GC compared to adjacent normal gastric tissues and that elevated amylin expression was negatively correlated with adverse pathological factors (p < 0.05). Additionally, we demonstrated that amylin impeded the growth, invasion, migration, and colony formation of GC cells and suppressed the epithelial-to-mesenchymal transformation of these cells (p < 0.05). Tumour xenograft model experiments confirmed the tumour-suppressive effect of amylin in subcutaneous tumours in nude mice (p < 0.05). Transcriptome sequencing (RNA-seq) revealed that amylin significantly down-regulated CCN1 gene expression in GC cells (p < 0.001). Further intervention targeting CCN1 verified its significance as a target of amylin's anti-carcinogenic function in GC. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that amylin exerted its oncogenic effects by inhibiting the PI3K/Akt signalling pathway (p < 0.05). CONCLUSIONS: Our findings demonstrate that amylin plays a crucial role in suppressing gastric cancer progression by targeting CCN1 and inhibiting the PI3K/Akt signalling pathway. These results suggest that amylin could serve as a potential therapeutic agent for GC treatment.

Humans↗

PubMed2026

Thyroxine enhances breast cancer cell survival and proliferation via TRβ1-Dependent PI3K/AKT signaling.

Thyroid hormones (TH) influence tumor biology through both genomic and non-genomic mechanisms. Specifically, thyroxine (T4) activates signaling pathways linked to cancer progression through interactions with nuclear receptors, such as TRβ1, and membrane receptors, including integrin αvβ3. Nevertheless, the precise role of T4 in breast cancer cell behavior and its underlying molecular mechanisms remain incompletely understood. The effects of physiological concentrations of T4 (10-9 M) on proliferation, cell viability, apoptotic signaling, and activation of intracellular pathways were evaluated in human mammary cell lines. Tumor cell lines (MCF-7 and MDA-MB-231) and the non-tumor mammary epithelial cell line MCF-10A were treated with T4 alone or in combination with the thyroid hormone receptor antagonist 1-850. Cell proliferation was measured using the MTT assay, and viability was determined by trypan blue exclusion. Protein expression and signaling pathways were analyzed by Western blot, including assessment of apoptotic markers (caspases, PARP, Bax, Bcl-2), PCNA, steroid hormone receptors, and signaling mediators such as PI3K, AKT, and ERK. Immunocytochemistry was used to evaluate TRβ1, integrin αvβ3, and Ki67 expression. T4 treatment increased proliferation and survival in hormone-sensitive tumor cells, accompanied by modulation of apoptosis-related proteins and activation of the PI3K/AKT pathway. The antagonist 1-850 selectively attenuated TRβ1-dependent effects, enabling distinction between genomic and integrin-mediated mechanisms. These effects were observed exclusively in hormone-sensitive tumor cells. These findings support a role for T4 in breast cancer progression and identify TH-related signaling pathways as potential therapeutic targets.

Apoptosis↗

PubMed2026

Inhibition of MAFB and PI3K/AKT Signaling for Hereditary FSGS with Multicentric Carpotarsal Osteolysis.

KEY POINTS: Multicentric carpotarsal osteolysis, a rare disorder, causes progressive osteolysis and kidney failure because of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene mutations. A genome-edited mouse model carrying the multicentric carpotarsal osteolysis mutation was used to obtain a deeper understanding of this rare disease. Targeting MAFB/IGF-1/PI3K/AKT signaling may provide new treatments for multicentric carpotarsal osteolysis-related nephropathy. BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) is a rare condition characterized by progressive osteolysis and often kidney failure. It is caused by autosomal dominant mutations in the transcription factor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ). METHODS: Given the absence of efficacious therapeutic interventions for MCTO and the obscurity of its pathophysiologic mechanisms, we used mice with the MCTO mutation ( MafbMCTO/MCTO mice) to explore the role of MAFB. RESULTS: MafbMCTO/MCTO mice displayed FSGS, mirroring the manifestations seen in patients with MCTO. These mice showed that the MCTO mutation leads to the accumulation of MAFB protein. Heterozygous MafbMCTO/- mice, generated by crossbreeding to reduce MAFB levels, neither exhibited albuminuria nor showed any histologic abnormalities in the kidney, suggesting that excess MAFB was detrimental. We subsequently conducted RNA-seq on the glomeruli from MafbMCTO/MCTO mice and detected pronounced upregulation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway through IGF-1. Given that receptor tyrosine kinases activate PI3K/AKT, we treated MafbMCTO/MCTO mice with the inhibitor imatinib. This led to a significant decline in urinary albumin levels compared with the control group. CONCLUSIONS: Our findings demonstrate that the MCTO mutation resulted in MAFB protein accumulation and led to the development of FSGS in mice.

Animals↗

PubMed2025

EIF2B5 promotes malignant progression of hepatocellular carcinoma by activating the PI3K/AKT signaling pathway through targeting RPL6.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options and poor prognosis. In this study, we demonstrated the critical role of EIF2B5 in driving HCC progression. We found EIF2B5 expression is significantly upregulated in HCC tumor tissues in several bioinformatics datasets, including The Cancer Genome Atlas, and that high expression of EIF2B5 predicts poor prognosis for HCC patients. Through a series of in vitro cell biology experiments, we found that EIF2B5 knockdown significantly attenuated Hep3B and HepG2 proliferation, migration, and invasion and increased cell cycle arrest, whereas EIF2B5 overexpression promoted HCC progression. Through mass spectrometry and immunoprecipitation validation, we found that EIF2B5 directly interacted with RPL6 and that when EIF2B5 was overexpressed in HCC cells, it promoted the expression of the downstream protein RPL6, which was able to activate the phosphatidylinositol kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and thereby increase the proliferation and invasion ability of HCC cell lines, as verified by second-generation sequencing analysis and western blot. We further verified these findings using the mouse ectopic tumor assay, and the results showed that EIF2B5 knockdown significantly inhibited tumor progression in HCC mice. The present study suggests that EIF2B5 promotes malignant progression of HCC by interacting with RPL6 and activating the PI3K/AKT/mTOR signaling pathway and may serve as a potential target for the treatment of HCC.

Humans↗

PubMed2026

Effects and mechanisms of Stauntonia brachyanthera Hand.-Mazz against Alzheimer's disease through network pharmacology and experimental validation.

Stauntonia brachyanthera Hand.-Mazz. (SB), a traditional medicinal plant of the Dong ethnic group with nutraceutical applications, exhibits broad-spectrum pharmacological activity. However, the therapeutic effects and mechanisms of SB on Alzheimer's disease (AD) remain unclear. This study aims to investigate the neuroprotective potential and underlying mechanisms of SB against AD. We utilized network pharmacology and molecular docking to predict the active components, targets, and pathways of SB associated with AD treatment. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were further used to identify potential therapeutic targets and underlying mechanisms of SB in relation to AD. Then, the neuroprotective effects, neuronal differentiation-promoting activity and potential mechanism of key active components of SB on the main therapeutic targets were verified by in vitro experiments. The network pharmacological prediction results showed that the treatment of AD with SB was closely related to MAPK and PI3K/Akt pathways. Further experiments showed that the SB active component kaempferol (KMF) alleviated Aβ1-42-induced injury and promoted neuronal differentiation. Additionally, we found that KMF-mediated promotion of neuronal differentiation in N2a cells was dependent on the PI3K/Akt and MAPK pathways. In this study, we employed a combined computational-experimental approach to elucidate the neuroprotective mechanisms of SB against Alzheimer's disease. We further validated KMF as a key active component of SB that alleviates Aβ1-42-induced injury and promotes neuronal differentiation through the PI3K/Akt and MAPK pathways.

Alzheimer's disease↗

PubMed2026

Network pharmacological and experimental validation of the mechanism of Chaihu Guizhi Ganjiang decoction regulating T helper cell 17/regulatory T cell balance to improve autoimmune hepatitis.

OBJECTIVE: To elucidate the therapeutic efficacy and mechanism of action of Chaihu Guizhi Ganjiang decoction (, CGGD) in autoimmune hepatitis. METHODS: CGGD components and potential target genes were extracted from previously published databases. The autoimmune hepatitis (AIH)-related regulatory genes were obtained from the DisGeNET database. Intersections were taken, and enrichment analyses were performed on the extracted data. Concanavalin A (ConA)-induced AIH model mice were treated with CGGD via gavage. The results of network pharmacological analysis were experimentally validated. RESULTS: Network pharmacology revealed 228 genes at the intersection of AIH and CGGD. Kyoto Encyclopedia of Genes and Genomes analysis revealed that CGGD primarily regulates the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway and cellular metabolism in AIH. Gene Ontology enrichment analysis revealed that CGGD modulates inflammation through transcription factor-mediated signaling pathways. As predicted, CGGD attenuated ConA-induced AIH in a dose-dependent manner by activating the PI3K/AKT signaling pathway. Histopathological assessment confirmed the protective effects of CGGD against ConA-induced AIH. Further investigation revealed that CGGD regulated the T helper cell 17 (Th17)/regulatory T cell (Treg) balance by modulating the PI3K/Akt/ nuclear factor kappa-B (NF-κB) pathway. CONCLUSIONS: This study demonstrated the therapeutic effect of CGGD on AIH through a combination of network pharmacological prediction and experimental validation. Its mechanism of action involves PI3K/Akt/ NF-κB-mediated regulation of Th17/Treg cells.

Animals↗

PubMed2026

TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses.

Asthma is a complex inflammatory airway disease with strong genetic determinants, yet the functional relevance of most asthma-associated non-coding variants remains unclear. Emerging evidence suggests that N6-methyladenosine (m6A) modification may serve as a critical epitranscriptomic link between genetic variation and immune regulation. In this study, we aimed to systematically identify functionally relevant m6A-regulated genes in asthma by integrating large-scale GWAS data, m6A-SNP annotations, and single-cell transcriptomic analyses, and to investigate their roles in monocyte-driven airway inflammation. We identified TET2 as a key m6A-regulated gene associated with both asthma and lung function, which was selectively upregulated in monocytes during asthma and accompanied by activation of inflammatory and PI3K signaling pathways. Mechanistic experiments further demonstrated that inflammatory stimulation induced ALKBH5 expression, reduced m6A modification of TET2 mRNA, and increased TET2 protein levels, thereby promoting PI3K/AKT signaling and pro-inflammatory cytokine production, whereas inhibition of TET2 or ALKBH5 attenuated these effects. Collectively, these findings demonstrate that ALKBH5-mediated m6A regulation of TET2 enhances PI3K/AKT signaling in monocytes, thereby promoting inflammatory responses in asthma. Our study establishes TET2 as a key m6A-regulated gene linking genetic susceptibility to monocyte-driven inflammation, and highlights the ALKBH5-m6A-TET2 axis as a potential therapeutic target for modulating aberrant immune responses in asthma.

Humans↗

PubMed2025

Integrated network pharmacology, molecular docking and experimental validation to investigate the mechanism of tannic acid in nasopharyngeal cancer.

Tannic acid (TA) is the primary bioactive component in the gallnut (Galla chinensis) and has exhibited the anticancer effects. However, the mechanism of its anti-cancer activity in nasopharyngeal carcinoma (NPC) remains unclear. This research aims to explore the underlying mechanism of TA in the treatment of nasopharyngeal cancer using network pharmacology, molecular docking and experimental validation. Firstly, the targets of TA and NPC were predicted and collected through databases, and the intersection targets were identified. Subsequently, protein-protein interaction (PPI) network analysis, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes Genomes (KEGG) pathway enrichment analysis, molecular docking and molecular dynamics (MD) simulation were conducted to uncover the potential mechanisms of TA in treatment of NPC. Finally, in vitro experiments were utilized to verify the mechanism of TA with anticancer activity in NPC. The results of network pharmacology revealed 42 intersection targets between NPC-related targets and TA-related targets. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was identified as the main target pathway of TA against NPC. Additionally, molecular docking and MD simulation confirmed the closely binding affinities of TA with AKT1. Furthermore, the results of in vitro experiments demonstrated that TA exerts anticancer activity against NPC by targeting the PI3K/AKT signaling pathway, leading to the suppression of cell proliferation. TA is a promising therapeutic candidate for NPC through PI3K/AKT signaling pathway. These results provide insights into the clinical application of TA, particularly when considered in combination with other therapeutic modalities.

Molecular Docking Simulation↗

PubMed2025

Proteomics uncovers ICAM2 (CD102) as a novel serum biomarker of proliferative lupus nephritis.

OBJECTIVES: This study aimed to identify novel, non-invasive biomarkers for lupus nephritis (LN) through serum proteomics. METHODS: Serum proteins were detected in patients with LN and healthy control (HC) groups through liquid chromatography-tandem mass spectrometry. The key networks associated with LN were screened out using Cytoscape software, followed by pathway enrichment analysis. The best candidate biomarkers were selected by machine learning models, further validated in a larger independent cohort. Finally, the expression of these candidate markers was verified in kidney tissue samples, and the mechanism was explored by knocking down the expression of intercellular adhesion molecule 2 (ICAM2) through in vitro cell transfection with siRNA. RESULTS: Following the serum proteomic screening of LN, a key network of 20 proteins was identified. Machine learning models were used to select ICAM2 (CD102), metalloproteinase inhibitor 1 (TIMP1) and thrombospondin 1 (THSB1) for validation in independent cohorts. ICAM2 exhibited the highest area under the curve (AUC) value in distinguishing LN from HC (AUC=0.92) and was significantly correlated with activity index, proteinuria, albumin and anti-dsDNA antibody levels. Particularly, ICAM2 was significantly elevated in proliferative LN and was associated with specific pathological attributes, outperforming conventional parameters in distinguishing proliferative LN from non-proliferative LN. ICAM2 expression was also elevated in renal tissue samples from patients with proliferative LN. In vitro, knockdown of ICAM2 expression can inhibit the activation of the PI3K/Akt pathway and alleviate the injury of glomerular endothelial cells. CONCLUSION: ICAM2 (CD102) may serve as a potential serum biomarker for proliferative LN that reflects renal pathology activity, potentially contributing to the progression of LN through the PI3K/Akt pathway.

Humans↗

PubMed2024

Effects of different temperatures on chondrocyte growth: a transcriptomic analysis.

BACKGROUND: Our previous study demonstrated that temperature-related microwave ablation (MWA) can safely modulate growth plates of piglets' vertebrae. Therefore, this study is designed to investigate the effects of different temperatures on chondrocyte viability and the underlying molecular mechanisms in vitro. METHODS: Following a 10-minute treatment at different temperatures (37 °C, 40 °C, 42 °C, 44 °C, 46 °C, 48 °C, and 50 °C), CCK-8 assay was used to examine the viability of ATDC5 cells at 12 h. Differentially expressed genes (DEGs) and the hub genes in ATDC5 cells treated at 37 °C, 40 °C and 44 °C were identified using RNA-seq. The expression of hub genes in ATDC5 cells was validated using RT-qPCR. RESULTS: Compared with 37 °C, exposure to 40 °C significantly increased the viability of ATDC5 cells, while 42 °C had no significant effect. Additionally, exposure to 44 °C, 46 °C, 48 °C, and 50 °C exhibited the opposite pattern, with ATDC5 cells being particularly less than 50% active after treatment at 46 °C, 48 °C, and 50 °C. Differential expression analysis identified 179, 374 and 221 DEGs in the comparisons of 40 °C vs. 37 °C, 44 °C vs. 37 °C, and 44 °C vs. 40 °C, respectively. These DEGs predominantly regulated proliferation, differentiation, necrosis, inflammatory and immune responses, and ECM synthesis/degradation. Furthermore, they were associated with the Ras, PI3K/AKT, mTOR, cAMP, and MAPK pathways. Agt, Hspa1a, Hspb1, and Nlrc4 were identified as hub genes in DEGs, and RT-qPCR confirmed that the mRNA expression patterns of these hub genes in ATDC5 cells were largely consistent with the RNA-seq results. CONCLUSION: The regulation of chondrocyte viability by temperature is associated with Ras, PI3K/AKT, mTOR, cAMP, and MAPK pathways. Additionally, Agt, Hspa1a, Hspb1, and Nlrc4 may be the key regulatory genes in this process.

Chondrocytes↗

PubMed2026

Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.

BACKGROUND: Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined. METHODS: To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism. RESULTS: PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth. CONCLUSION: PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.

Journal Article↗

PubMed2026

PCSK9 as a Key Gene of Metastasis in Lung Adenocarcinoma: A Multi-omics and Experimental Validation Study.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common form of lung cancer. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is abnormally expressed in various tumor tissues and is associated with malignant phenotypes. However, the clinical significance, function, and mechanism of LUAD invasion and metastasis remain unclear. METHODS: We retrospectively enrolled 100 patients with LUAD in this study. Initially, qRT-PCR was performed to detect PCSK9 levels in clinical tissues. Subsequently, bioinformatics analysis of scRNA-seq and The Cancer Genome Atlas Program (TCGA) datasets was performed to predict the role of PCSK9 in tumor cell malignancy and its potential downstream pathways. These predictions were validated experimentally using the CCK-8 assay, TUNEL staining, wound healing, transwell invasion assay, and an in vivo lung metastasis model. Finally, Western blotting and an AKT inhibitor (MK2206) were used to verify the underlying mechanism. RESULTS: PCSK9 was significantly upregulated in LUAD tissues compared to paracancerous tissues and was associated with poorer OS and DFS. Bioinformatics analysis of scRNA-seq data and TCGA analysis predicted that PCSK9 is highly enriched in tumor cells and is involved in EMT, and that the PI3K/AKT pathway plays a significant role in LUAD development. Experiments confirmed that PCSK9 markedly promoted LUAD cell proliferation, migration, and invasion in vitro and lung metastasis in vivo. PCSK9 overexpression significantly upregulated p-AKT, p-PI3K, and p-mTOR levels. Furthermore, the AKT inhibitor, MK2206, reversed the promoting effects of PCSK9. CONCLUSIONS: PCSK9 expression is associated with the prognosis and diagnosis of LUAD. This molecule activates the PI3K/AKT signaling pathway, thereby driving invasion, metastasis, and proliferation in LUAD.

Humans↗

PubMed2026

The Germline SH2B3rs111340708 Splicing Variant Drives Intron Retention and Protein Instability by Impacting Clinical Outcomes in Core Binding Factor AML.

The SH2B3 gene, also known as LNK, encodes an adaptor protein that negatively regulates key hematopoietic signaling pathways, including JAK-STAT, MAPK, and PI3K/AKT, thereby maintaining hematopoietic homeostasis. SH2B3 interacts with major signaling regulators such as JAK2, MPL, FLT3, and KIT. Loss-of-function alterations have been reported in several hematologic malignancies, supporting its role as a leukemia predisposition gene. We previously identified a germline start-loss mutation (c.3G > A) in SH2B3 in a family with early-onset myeloproliferative neoplasm, demonstrating that this variant causes SH2B3 haploinsufficiency. In the present study, next-generation sequencing of 149 de novo AML patients identified a frequent intronic polymorphism (rs111340708), located within intron 6 (IVS6) of SH2B3. Although this variant has a reported minor allele frequency (MAF) of approximately 12% in European populations, it was enriched in our AML cohort, reaching 34.2% in Core Binding Factor leukemias (CBFLs). The presence of the rs111340708 variant was associated with inferior overall survival, whereas no significant association with progression-free survival was observed. Functional analyses demonstrated that this polymorphism promotes aberrant IVS6 intron retention in AML cells, resulting in reduced abundance of correctly spliced SH2B3 transcripts and predicted generation of truncated peptides and/or nonsense-mediated decay. Consistently, immunoblot analyses of AML patient samples and hematologic cell lines revealed heterogeneous SH2B3 protein expression, including additional SH2B3-immunoreactive species in variant carriers, together with reduced levels of the canonical SH2B3 protein. Collectively, these findings identify a common germline splicing polymorphism as a novel mechanism contributing to SH2B3 functional impairment in AML and highlight the potential relevance of non-coding variants in leukemia pathogenesis, with possible implications for risk stratification and future therapeutic strategies.

Humans↗

PubMed2026

Mechanism of Shoutai Wan against recurrent spontaneous abortion: regulation of decidual vascular remodeling via ERβ-ANGPT2 signaling axis.

Shoutai Wan (STW), a classic traditional Chinese medicine formula used to tonify the kidney and prevent miscarriage, has been widely applied in the clinical management of recurrent spontaneous abortion (RSA). Increasing clinical evidence supports its efficacy in reducing miscarriage rates and improving pregnancy outcomes. However, the molecular basis by which STW alleviates defective decidual vascular remodeling in unexplained RSA remains insufficiently understood. Clinically, decidual ERβ and ANGPT2 expression, as well as serum estradiol, ANGPT2 and VEGFA levels were significantly decreased in RSA patients, accompanied by reduced decidual microvascular density. Furthermore, ERβ expression was positively correlated with ANGPT2 and microvascular density. In vivo, STW dose-dependently reduced embryo loss in RSA mice, repaired the damaged decidual-placental interface structure, and improved vascular maturation, structural stability and endothelial-pericyte ultrastructural connections. Mechanistically, STW upregulated ERβ expression. We demonstrated that ERβ binds to the ANGPT2 promoter, suggesting transcriptional upregulation of ANGPT2, thereby activating Tie2 and the downstream PI3K/AKT pathway and increasing NO and VEGFA secretion. In vitro, hypoxia inhibited ERβ nuclear translocation and ANGPT2 secretion in mDSCs, while STW-containing serum reversed these abnormalities. ERβ knockdown impaired the pro-angiogenic capacity of mDSCs, which was partially rescued by exogenous ANGPT2 supplementation. Network pharmacology predicted that STW targets were mainly enriched in PI3K-Akt, estrogen, VEGF and angiogenesis-related pathways. Transcriptomic GSEA further revealed that the gene signatures of angiogenesis and PI3K-Akt signaling were markedly suppressed in the RSA model, and STW treatment significantly normalized these transcriptional signatures.

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