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To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained from the UK Biobank Pharma Proteomics Project, FinnGen, and the Million Veteran Program. We used a four-stage analytical framework: Stage 1 applied Mendelian randomization and Bayesian colocalization to evaluate associations between 2923 plasma proteins and glaucoma; Stage 2 used summary-based Mendelian randomization to explore transcriptomic and epigenomic associations of the identified proteins with glaucoma risk; Stage 3 involved a prospective association analysis of protein levels and incident glaucoma in the UK Biobank cohort, including 40,170 glaucoma-free participants; and Stage 4 systematically evaluated the druggability of the prioritized protein targets. We identified 26 plasma proteins with putative causal associations with glaucoma, six of which were novel: COL24A1, KAZALD1, EBAG9, CSNK1D, AZI2, and AXIN1. COL24A1 (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.80-0.90; PFDR < 0.001; PP.H4 = 0.95) and EFEMP1 (OR = 0.88; 95% CI, 0.83-0.92; PFDR < 0.001; PP.H4 = 0.98) emerged as the most compelling candidates. To further elucidate the regulatory mechanisms, multiomics analyses indicated that epigenetic modifications and alternative splicing events affecting these genes were associated with elevated glaucoma risk. Notably, EFEMP1 was significantly associated with glaucoma incidence in the prospective cohort analysis (fully adjusted Cox model: hazard ratio = 1.61; 95% CI, 1.29-2.00; PFDR = 0.002), demonstrating strong predictive performance (C-index = 0.811, area under the curve = 0.806) and representing a promising therapeutic target. Our findings provide new insights into the proteomic basis of glaucoma and highlight promising opportunities for developing targeted therapies. Show less

Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. However, its regulatory mechanism and pathobiological roles in EC remain unclear. Rab35 expression in EC was systematically profiled via integrative analysis of clinical endometrial specimens and multi-omics databases (CPTAC and GEO). The association between clinical prognosis and Rab35 expression was examined using Kaplan-Meier analysis. Mechanistic investigations included transwell assays, western blotting, and immunofluorescence in Rab35-overexpressing and CRISPR/Cas9-mediated Rab35-knockout EC cells. A mouse xenograft tumor model was established to confirm the effects of Rab35 in vivo. The Rab35 content increased gradually from normal endometrium to atypical hyperplastic endometrium to EC. Moreover, the findings indicated that elevated Rab35 expression was significantly associated with advanced disease characteristics and poor overall survival in patients with EC. In addition, Rab35 enhanced the migratory and invasive nature of EC cells. The expression of Rab35 was inversely linked to that of the β-catenin destruction complex-related proteins Axin-1 and GSK3β, leading to the increased nuclear translocation of β-catenin in EC cells. Animal experiments further verified that Rab35 augmented EC progression by regulating the nuclear translocation of β-catenin. The study revealed that high expression of Rab35 was strongly correlated with EC progression and a poor clinical outcome. Furthermore, Rab35 promoted EC cell metastasis by accelerating the nuclear translocation of β-catenin. These findings suggest that Rab35 serves as a valuable biomarker and therapeutic target for EC. Show less

Despite the emerging role of the gut microbiome in colorectal cancer (CRC), its significance in early-onset CRC (EOCRC, < 50 y) versus late-onset CRC (LOCRC) and the molecular differences between proximal and distal CRC remain poorly understood. To circumvent the logistical and patient compliance challenges of stool collection, we explored the utility of anal swabs as a convenient alternative for characterizing gut microbiome signatures in CRC. We profiled the CRC microbiome using anal swabs ( Show less

The causal links between gut microbiota, inflammatory cytokines, and chronic rhinosinusitis are unclear. A Mendelian randomization study used data from the MiBioGen consortium (211 microbiota taxa, n = 18,340), genome-wide association studies of 91 inflammatory cytokines, and chronic rhinosinusitis data from the FinnGen consortium. Five microbiota taxa were causally linked to chronic rhinosinusitis. The genera Ruminococcaceae NK4A214 group and Victivallis were risk factors, while Lachnospiraceae NC2004 group, Ruminococcus2, and Subdoligranulum were protective. Elevated levels of axin-1, C-X-C motif chemokine 10, interleukin-18 receptor 1, interleukin-1-alpha, and vascular endothelial growth factor A increased risk, whereas C-C motif chemokine 19, CD40L receptor, and Fractalkine were protective. The Ruminococcaceae NK4A214 group id.11358 increased risk through reduced Fractalkine and elevated vascular endothelial growth factor A levels. The study supports a causal link between Ruminococcaceae NK4A214 group id.11358 and chronic rhinosinusitis, mediated by Fractalkine and vascular endothelial growth factor A levels. Show less

To ensure high phototransduction efficiency in the retina, the precise subcellular localization of signaling molecules must be tightly orchestrated by scaffold proteins. Aberrant localization of these scaffold proteins not only disrupts the transition of photoelectrical signals but also triggers endoplasmic reticulum (ER) stress, which leads to photoreceptor apoptosis. However, it is unknown how these proteins are localized to specific subcellular compartments of photoreceptors or how protein mislocalization is coupled with apoptotic signaling. Herein, we observed a specific spatiotemporal expression pattern of the scaffold protein, Axin1, in the mouse retina. We found that Axin1 is essential for the retinal localization of S-opsin chromoprotein in the outer segment of photoreceptors. Moreover, retinal Axin1 deficiency disrupts light perception, accompanied by cone photoreceptor loss and ER stress. In addition, knockdown of Axin1 exacerbates ER stress-induced apoptosis of cone-derived 661W cells. Consistently, pharmacological elevation of Axin1 protein level alleviates tunicamycin-induced ER stress and apoptosis via inhibition of GSK3β activity. Thus, our findings demonstrate that Axin1 plays a pivotal role in organizing the phototransduction complex and ensuring photoreceptor survival in the retina. Show less

It is known that insulin stimulates skeletal muscle glucose uptake via the InsR-IRS-PI3K pathway. The signaling downstream of PI3K is divided into the Akt-AS160-Rabs branch and the Rac1-actin cytoskeleton branches. These two signaling branches jointly mediate the effect of insulin to promote GLUT4 transporters to transport glucose into the cell. The scaffolding protein Axin1 plays a crucial role in maintaining glucose homeostasis and TNKS, a member of the PARP family, is involved in insulin-stimulated GLUT4 translocation. However, the specific roles of Axin1 and TNKS and their relationship are elusive in insulin-stimulated skeletal muscle cell glucose uptake. Here, we showed that insulin up-regulated the protein levels of Axin1 and TNKS in an Akt-dependent manner in C2C12 skeletal muscle cells. Knockdown of Axin1 inhibited insulin-stimulated GLUT4myc translocation in C2C12-GLUT4myc myotubes. Both over-expression Axin1 and TNKS activity inhibitor XAV939 enhanced insulin-stimulated GLUT4myc translocation. XAV939 up-regulated Axin1 and TNKS protein levels. Knockdown or over-expression of Axin1 down- or up-regulated the protein level of TNKS, respectively. Axin1 interacted with TNKS which was enhanced by insulin. Knockdown of Axin1 inhibited insulin-induced the phosphorylation of the Rac1 target protein PAK. Over-expression of Axin1 and XAV939 increased insulin-phosphorylated PAK. Up- and down-regulation of Axin1 and XAV939 had no effects on the phosphorylation of Akt and AS160. Insulin increased the Rac1-GEF Tiam1 protein levels. Knockdown of Tiam1 diminished insulin-stimulated PAK phosphorylation and GLUT4myc translocation. Knockdown of Axin1 inhibited insulin-induced Tiam1 expression, while over-expression of Axin1 and XAV939 had the opposite effect. In summary, our results suggest that an Akt-Axin1/TNKS-Tiam1-Rac1 signaling pathway mediates insulin-stimulated GLUT4 translocation in skeletal muscle cells. Show less

WNT-β-catenin activation is observed in around 50% of all patients with hepatocellular carcinoma (HCC), through either gain-of-function mutations in CTNNB1 (which encodes β-catenin) or loss-of-function mutations in AXIN1 or APC. Currently, first-line therapies for HCC are immune checkpoint inhibitor (ICI) combinations, and β-catenin-active HCCs have garnered increased attention due to their unique tumour immune microenvironment (TIME). This pathway is known to drive an immune-excluded TIME, but clinical investigations have provided a more nuanced perspective, with the emergence of a new 'immune-like' subclass of HCC that is paradoxically enriched for CTNNB1 mutations and has high levels of T cell infiltration. As such, patients and animal models with β-catenin activation treated with ICIs exhibit heterogeneous responses. Additionally, these tumours exhibit higher fatty acid oxidation to fuel tumour growth owing to a unique metabolic milieu shaped by zone 3 metabolism, which is a physiological function of WNT-β-catenin signalling in the liver lobule. Biomarkers to detect molecular subclasses of patients for targeted therapies are being developed. In this Review, we discuss advances in our understanding of the TIME and metabolism of β-catenin-active HCC, driven by in vitro and in vivo models and single-cell and spatial sequencing, and their implications for the treatment of a subset of HCCs using precision therapies against WNT-β-catenin signalling. Show less

AXIN1 (axis inhibition protein 1), as a rate-limiting component of canonical Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin signaling pathway, may influence midbrain dopaminergic neurons. A recent genome-wide association study identified AXIN1 as a candidate gene for Parkinson's disease (PD). Our study aimed to investigate the potential relevance of AXIN1 single nucleotide polymorphisms (rs13337493 and rs9921222) in the risk, clinical characteristics, and pathology of PD. Data were collected from the Northern Han Chinese and Parkinson's Progression Markers Initiative (PPMI) cohorts. Associations between AXIN1 variants, PD-related biomarkers, and clinical manifestations were analyzed. Both loci were identified as risk factors in the Northern Han Chinese population, and the A allele of rs13337493 [odds ratio (OR) 1.320, 95% confidence interval (CI) 1.052, 1.653, P Our findings support a gatekeeper role for AXIN1; its polymorphisms contribute to increased PD susceptibility and accelerated motor progression, yet may also trigger a compensatory presynaptic response, as evidenced by elevated CSF DOPA levels, to counteract neurodegeneration. Future studies should include larger sample sizes, more diverse ethnic populations, and protein-level investigations. Show less

Dibutyl phthalate (DBP) is a member of phthalate esters which are considered as potent environmental toxicant owing to their damaging effects on different organs including testis. Glabridin (GLN) is a polyphenolic substance that is found in the roots of Glycyrrhiza glabra and exhibits a wide range of pharmacological activities. This research investigation explored the ameliorative potential of GLN against DBP instigated testicular toxicity. Forty-eight male Sprague Dawley rats were categorized into control, DBP (200 mg/kg), DBP (200 mg/kg) + GLN (50 mg/kg), and GLN (50 mg/kg) group. We found that DBP administration exacerbated the gene expression of β-catenin, WNT1, and TCF7L2 while suppressed the gene expression of APC, AXIN1 as well as GSK3β. Furthermore, DBP exposure promoted the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) while suppressing the activities of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), glutathione reductase (GSR), glutathione Peroxidase (GPx), catalase (CAT), and glutathione (GSH). Moreover, DPB administration exacerbated Caspase-9, Bax and Caspase-3 while diminishing Bcl-2 concentrations. A notable escalation was observed in the levels of interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and nuclear factor- kappa B (NF-κB) following the administration of DBP. Besides, DBP intoxication distorted the normal morphology of testicular tissues. Nonetheless, GLN therapy significantly alleviated testicular impairments via regulating aforementioned biochemical and histological abnormalities. These findings suggest he palliative efficacy of GLN against DPN induced testicular damages thereby recommending the use of GLN to promote reproductive health in male. Show less

Mild depression in women is a distinct disorder with unclear immune mechanisms. This study aims to identify peripheral inflammatory biomarkers and to explore acupuncture's immunomodulatory effects via Olink proteomics. Thirty female participants (18-45 years) were assigned to healthy controls (HC), mild depression (MD), and acupuncture treatment (ACU). Plasma samples were analyzed using the Olink https://www.chictr.org.cn/showprojEN.html?proj=189355, identifier ChiCTR2300068054. Show less

To investigate the causal relationship between inflammatory proteins and Alzheimer's disease (AD) and the mediating role of plasma metabolites therein. Using Mendelian mandomization (MR) methods and publicly available genome-wide association study (GWAS) data, we selected 91 single nucleotide polymorphisms (SNPs) that were strongly linked to inflammatory proteins without reverse causality with AD as the outcome. A bidirectional two-sample MR analysis was performed. Inflammatory proteins with causal links to AD were identified via inverse variance weighted (IVW) analysis. A mediation MR analysis was then performed using 1400 plasma metabolites to assess their mediating role in this causal pathway. The preliminary bidirectional MR analysis identified 3 inflammatory proteins that had a potential positive causal association with AD without reverse causality: Axin-1, C-X-C motif chemokine ligand 11 (CXCL11), and interleukin-12β (IL-12β). Elevated levels of Axin-1 were positively causally associated with AD risk (OR=1.082, 95% This study reveals how specific inflammatory proteins influence AD risk via plasma metabolites and provides genetic evidence for inflammatory-metabolic interactions in AD to facilitate the identification of potential biomarkers and targets for early detection and intervention of AD. Show less

Biallelic DIAPH1 mutations are linked to hereditary microcephaly syndrome, yet the underlying pathogenic mechanism remains unelucidated. This study aimed to clarify how DIAPH1 biallelic mutations cause microcephaly and visual impairment, focusing on the gene's regulatory role in the Wnt/β-catenin signaling pathway. Whole exome sequencing was performed on a patient's peripheral blood to identify DIAPH1 mutations. A zebrafish model was established by microinjecting mutant human DIAPH1 cDNA into one-cell embryos (no zebrafish DIAPH1 homolog exists). Phenotypic analyses (morphology, neuronal axon growth, behavior) and quantitative real-time PCR for Wnt/β-catenin pathway genes were conducted. Data were mean ± SEM; statistical tests (Student's t-test, ANOVA, χ²) used GraphPad Prism 5.0 (P < 0.05, P < 0.0001 for significance). Compound heterozygous DIAPH1 mutations (c.1051 C > T, p.R351X; c.609delA, p.E203E fs*19) were found and associated with clinical symptoms. Mutant DIAPH1 zebrafish showed abnormal eye shape, shortened body length, axis defects, impaired motor axon growth, reduced locomotor activity, upregulated WNT8A, WNT9A, LRP5, LRP6, and downregulated AXIN1, AXIN2, β-CATENIN, indicating excessive Wnt/β-catenin pathway activation. DIAPH1 compound heterozygous mutations may trigger microcephaly and visual impairment by abnormally activating the Wnt/β-catenin pathway. The zebrafish model provides a reliable in vivo system for studying DIAPH1-related microcephaly, advancing understanding of hereditary primary microcephaly pathogenesis and potential therapeutic target exploration. Show less

Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD. In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated. Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice. Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD. Show less

Nucleoporins are increasingly recognized as tissue-specific regulators beyond their structural roles in the nuclear pore complex. Here, we identify nucleoporin Nup358 as a critical repressor of Wnt signaling required for intestinal epithelium integrity. Ablation of Nup358 in adult mice causes a catastrophic loss of crypt-villus architecture and disrupts the intestinal epithelial layer. Notably, while the intestinal stem cell (ISC) pool remains stable, the transit-amplifying (TA) progenitor compartment is depleted. Mechanistically, we show that the interaction of Nup358 with Dvl1 through its N-terminal domain inhibits Dvl1 spontaneous phase separation. In the absence of Nup358, Dvl1 biomolecular condensates promote Tankyrase-mediated degradation of Axin1, leading to the constitutive stabilization of β-catenin and ligand-independent Wnt activation, negatively impacting cell differentiation and TA progenitor survival. Our results demonstrate that Nup358 acts as a molecular safeguard that dampens Wnt signaling levels in intestinal crypts. By preventing Dvl1-mediated Wnt signal amplification, Nup358 allows ISCs to transition into the TA compartment and initiate the differentiation programs essential for intestinal homeostasis. Show less

Previous studies indicate associations between inflammatory cytokines and glioma, meningioma, and astrocytoma. We conducted two-sample Mendelian randomization with genetic data for tumors from FinnGen R10 and cytokine data from GWAS. Primary analysis used inverse variance weighting, supplemented by sensitivity analyses including weighted median, simple mode, weighted mode, and MR-Egger. For glioma, TNF-related apoptosis-inducing ligand (TRAIL) was a risk factor, while Fibroblast growth factor 21 (FGF21) was protective. For meningioma, Axin-1 and Matrix metalloproteinase-1 were risk factors, whereas Fms-related tyrosine kinase 3 ligand was protective. For astrocytoma, risk factors included Eotaxin, Macrophage colony-stimulating factor 1, and Interleukin-8; protective factors were T-cell surface glycoprotein CD5 and Tumor necrosis factor ligand superfamily member 12. This Mendelian randomization study identified specific inflammatory cytokines associated with these tumors, providing direction for future mechanistic research. Show less

Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin-destruction complex (GSK3 β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target. Show less

CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or "Other" genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1-mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new "progressed pattern" associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1, APC, and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change. Show less

Most cancer cells rely on aerobic glycolysis to support uncontrolled proliferation and evade apoptosis and switch to glutamine metabolism to survive under hypoxic conditions. In hepatocellular carcinoma (HCC), the Wnt/β-catenin pathway acts as a critical driver of metabolic reprogramming and stemness, primarily by enhancing aerobic glycolysis and altering the tumour microenvironment. The Wnt/β-catenin pathway induces activation of enzymes required for glucose metabolism and regulates the expression of glutamate transporter and glutamine synthetase. The objective of this study is to examine the mechanism by which riluzole inhibits HCC growth and induces autophagy. The results indicate that riluzole inhibits cell viability and colony formation of HCC cells and cancer stem cells (CSCs) and induces apoptosis, while sparing human normal hepatocytes. Riluzole induces autophagic cell death by inducing Beclin1 and Atg5. Riluzole inhibits β-catenin, Wnt3a, Wnt5a, Axin1, TCF, LEF and GSK3β expression, and TCF/LEF activity in HCC cells. Inhibition of the Wnt-β-catenin/TCF-LEF pathway by riluzole suppresses the expression of Cyclin D1, Axin2, cMyc, MCT1 and DNMT1. Riluzole inhibits the expression of Glut1 and Glut3, PDK1, LDHA and PKM2, glucose uptake and NAD+ levels. Furthermore, riluzole inhibits glutamate release, which reduces the antioxidant glutathione, leading to increased reactive oxygen species (ROS). Riluzole disrupts mitochondrial homeostasis by increasing Bax/Bcl-2 ratio, resulting in a drop of mitochondrial membrane potential. In conclusion, riluzole inhibits HCC growth by regulating glucose and glutamine metabolism and inducing autophagic cell death, thereby highlighting its therapeutic potential for HCC treatment. Show less

APC, the core scaffold of the Wnt destruction complex, targets the transcriptional co-activator β-catenin for proteolysis. There is no convincing evidence that APC directs degradation of other substrates. Using a reconstituted cytosolic extract-based system and complementary in vivo and cellular assays, we show that SREBP2, the master regulator of cholesterol biosynthesis, is a direct APC-AXIN1 substrate. APC-dependent SREBP2 degradation is conserved in Show less

Cribriform morular thyroid carcinoma (CMTC) is a rare malignant thyroid carcinoma, mainly seen in young Asian women. CMTC is related to the activation of the WNT/β-catenin signaling pathway, so CMTC is usually closely related to familial adenomatous polyposis (FAP). The patient was a 13-year-and-11-month-old girl with a right neck mass. After total thyroidectomy and bilateral lymph node dissection, the tumor's pathological report is CMTC, and 31 lymph nodes exhibited metastatic carcinoma. Adenomatous polyposis coli (APC) gene mutation has been detected. CMTC has typical cribriform and morular structures under microscope. It is associated with the WNT/β-catenin signaling pathway through inactivating mutations in the APC, CTNNB1, and AXIN1 genes, thereby enabling WNT gene expression and participating in proliferation, invasion, dedifferentiation, and tumorigenesis. CMTC is usually closely related to FAP. It requires clinical attention, and the patient's intestinal condition still needs to be closely monitored after surgery. Show less

Axin1 plays a critical role in regulating the Wnt/β-catenin signaling pathway and cancer progression, and its polymerization is indispensable for the assembly of the β-catenin destruction complex. However, the mechanisms that control Axin1 polymerization are limited. Here, we reveal that TRIM15 interferes with the polymerization of Axin1, thereby promoting Wnt activation and colorectal cancer growth. Mechanistically, TRIM15 strongly interacts with Axin1 through its coiled-coil domain to disrupt the polymerization among Axin1 molecules. Manipulation of TRIM15 expression dramatically weakens Wnt signaling, cell proliferation, and tumor growth. Furthermore, conditional genetic ablation of Trim15 in mice inhibits tumor formation in both AOM/DSS-induced and Apc Show less

The Wnt/β-catenin signaling pathway is a classical pathway that regulates bone metabolism. The G protein inhibitory α subunits 1 and 3 (Gαi1/3) can couple with multiple growth factor/cytokine receptors and act as universal adaptor proteins to mediate the activation of key downstream signaling pathways. However, it remains unclear whether and how Gαi1/3 proteins mediate Wnt/β-catenin signal transduction. In this study, we utilized single-cell sequencing analysis and employed viral transfection and gene editing techniques to alter the expression of Gαi1/3 in mouse embryonic osteoblast precursor cells. We examined the relationship between Gαi1/3 expression and the Wnt/β-catenin signaling pathway. Immunoprecipitation and confocal experiments were conducted to further explore the mechanisms by which Gαi1/3 exerts its functions. Osteogenic-related protein levels were detected by Western blotting, and the effects of Gαi1/3 proteins on osteogenic function were examined through alkaline phosphatase and Alizarin red staining. Additionally, micro-CT was used to compare bone mass in mice with different levels of Gαi1/3 expression, showing the relationship between Gαi1/3 and bone formation. Our findings indicate that Gαi1/3 proteins are significantly inversely correlated with age. Gαi1/3, rather than Gαi2, mediates the Wnt/β-catenin signaling pathway and promotes osteogenesis. Mechanistically, Gαi1/3 interacts with Axin1 and recruits it to the cell membrane, leading to inactivation of the β-catenin degradation complex. This results in β-catenin accumulation and nuclear translocation, where it activates the transcription of osteogenic genes. In vivo experiments further confirm that knockdown of Gαi1/3 significantly inhibits bone formation in mice. Our study identified Gαi1/3 as key regulatory proteins in Wnt/β-catenin signaling-mediated osteogenesis, and further elucidated its molecular mechanism in bone formation, which may provide a new therapeutic target for osteoporosis. Show less

Previous observational studies have highlighted a significant link between dyslipidemia and kidney stones. However, whether plasma lipid composition directly influences kidney stone formation and the extent to which inflammatory proteins mediate this relationship remain uncertain. This study utilizes genetic variation data from the recent genome-wide association studies to analyze 179 plasma lipids and 91 inflammatory proteins in relation to kidney stones. By applying a two-sample Mendelian randomization (MR) approach, we systematically investigated the potential causal effects of plasma lipids on kidney stones and assessed the mediating role of inflammatory proteins through a two-stage MR analysis. The findings revealed that specific phosphatidylcholines (PC) (including PC(14:0₁₈:1), PC(16:0₂₀:2), PC(16:1₁₈:0), and PC(18:0₁₈:3)) exhibited positive causal associations with kidney stone risk, while sterol esters (27:1/18:0) demonstrated stone risk-reducing effects. Among inflammatory proteins, monocyte chemoattractant protein 2 and tumor necrosis factor ligand superfamily member 14 (TNFSF14) were associated with increased kidney stone risk, whereas Axin-1, macrophage colony-stimulating factor 1, C-X-C motif chemokine 10, interleukin-5, and urokinase-type plasminogen activator (uPA) correlated with reduced risk. Further mediation analysis revealed that TNFSF14 and uPA may serve as mediators in the relationship between the plasma lipidome and kidney stone formation. This study provides insights into the mechanisms by which plasma lipid metabolism influences kidney stone development through inflammatory regulatory networks. These findings lay a theoretical foundation for lipidomics- and inflammation-based biomarker risk prediction, as well as targeted intervention strategies for kidney stone prevention. Show less

The β-catenin destruction complex (BDC) is a central node in WNT/β-catenin signaling, governing embryonic development and adult tissue homeostasis. Although recognized as a prime therapeutic target in colorectal cancer (CRC) for three decades, its dynamic architecture and biochemical complexity have hindered mechanistic understanding. Here, we systematically mapped the sequence-function landscape of the BDC using tiled base editor screens across four endogenous components- Show less

Evidence is accumulating that links gut microbiota, a crucial component of the immune environment, to Sjogren's syndrome (SS). The mechanisms underlying the influence of gut microbiota on the onset and development of SS are still not completely understood. To this end, we applied a Mendelian randomization (MR) framework to investigate whether inflammatory cytokines mediate the association of gut microbiota with SS. Our MR analysis leveraged publicly available GWAS data, including information on 211 gut microbiota taxa sourced from the MiBioGen consortium (18,340 participants), summary statistics for 91 inflammatory cytokines obtained from a study of 14,824 individuals, and genetic data for SS derived from the UK Biobank (407,746 participants). To investigate causal associations between gut microbiota and SS, we primarily employed the inverse variance weighted method, supported by additional techniques such as MR-Egger, simple mode, weighted median, and weighted mode for validation. The potential mediating effect of inflammatory cytokines in the gut microbiota-SS relationship was investigated using both mediation MR and multivariable MR (MVMR) analyses. MR analysis identified five microbiota taxa causally associated with SS. Particularly, class Gammaproteobacteria (OR = 3.468, 95% CI = 1.139-10.557, The findings suggest that certain gut microbiota is sociated with an increased risk of SS, mediated by specific inflammatory cytokines. Show less

Hepatocellular carcinoma (HCC) arises from various etiologies, including viral hepatitis and non-viral liver diseases. Although comprehensive genomic profiling (CGP) is increasingly applied in oncology, the influence of disease etiology on the genomic landscape of HCC and biomarker applicability remains insufficiently characterized. CGP data from 551 patients with HCC, registered in the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, were analyzed after excluding cases with undefined etiology. We characterized the mutational landscape, compared mutation frequencies among HBV-, HCV-, and non-viral, non-cholestatic (nBnC)-related HCC, assessed the association between homologous recombination repair (HRR)-related gene alterations and tumor mutation burden (TMB), and evaluated the detection rates of actionable mutations in tissue- versus liquid-based CGP. Telomerase reverse transcriptase splice site mutations were the most common genomic alteration and were consistently observed across all etiologic groups. Although mutations in AXIN1 and DDR2 genes showed modest enrichment in HCV- and HBV-related HCC, respectively, the overall mutational profiles remained largely conserved across etiologies. TMB was significantly lower in nBnC-HCC compared to HCV-related HCC but showed no association with HRR-related mutations. The detection rates of targetable mutations were similar between tissue and liquid biopsies; however, only a small proportion of patients received matched therapies. Real-world data indicate a conserved genomic architecture in HCC regardless of etiology, supporting unified therapeutic approaches. The absence of a relationship between HRR alterations and TMB suggests distinct biological mechanisms. Liquid biopsy remains a reliable option when tissues are unavailable in managing patients with HCC. Show less