Endocytosis is essential for cancer cell motility, which is predominantly mediated by the sorting nexin (SNX) family. Previous studies have demonstrated that SNX5 is elevated in several tumors, while its clinical significance and underlying mechanism in gastric cancer (GC) remain uninvestigated. In this study, we reported that SNX5 is highly expressed in GC and promotes the malignant biological behavior of GC cells. Its upregulation is closely related to poor prognosis in GC patients. Mechanistically, we observed an interaction between SNX5 and low-density lipoprotein receptor-related protein5 (LRP5) in GC cells. SNX5 inhibits LRP5 internalization and promotes its recycling to the cell membrane, which prevents LRP5 from being degraded in the lysosome. The increased membrane localization of LRP5 facilitates β-catenin stabilization, thus activating the Wnt signaling pathway, leading to tumorigenesis and progression.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in the world, and its incidence and mortality have increased year by year. HCC research has increasingly focused on understanding its pathogenesis and developing treatments.The Wnt signaling pathway, a complex and evolutionarily conserved signal transduction system, has been extensively studied in the genesis and treatment of several malignant tumors. Recent investigations suggest that the pathogenesis of HCC may be significantly influenced by dysregulated Wnt/β-catenin signaling. This article aimed to examine the pathway that controls Wnt signaling in HCC and its mechanisms. In addition, we highlighted the role of this pathway in HCC etiology and targeted treatment.

Cancer is one of the most significant public health challenges in the new millennium, and complex mechanisms are at work to contribute to its pathogenesis and progression. The Wnt signaling pathways, which are crucial conserved cascades involved in embryological development and tissue homeostasis, and mitochondria, the intracellular powerhouses responsible for energy production, calcium and iron homeostasis, as well as mitochondrial apoptosis in eukaryotic cells, have their own mechanisms regulating these pathological processes. In the past decade, accumulating evidence has indicated that Wnt signaling pathways directly regulate mitochondrial biogenesis and function under physiological and pathological conditions. In this review, we systemically summarize the current understanding of how Wnt signaling pathways, particularly the canonical Wnt cascade, regulate mitochondrial fission, respiration, metabolism, and mitochondrial-dependent apoptosis in cancer. In addition, we discuss recent advancements in the research of anticancer agents and related pharmacological mechanisms targeting the signaling transduction of canonical Wnt pathway and/or mitochondrial function. We believe that the combined use of pharmaceuticals targeting Wnt signaling and/or mitochondria with conventional therapies, immunotherapy and targeted therapy based on accurate molecular pathological diagnosis will undoubtedly be the future mainstream direction of personalized cancer treatment, which could benefit more cancer patients.

Most persons with colorectal cancer (CRC) carry adenomatous polyposis coli (APC) truncation leading to aberrant Wnt-β-catenin signaling; however, effective targeted therapy for them is lacking as the mechanism by which APC truncation drives CRC remains elusive. Here, we report that the cholesterol level in the inner leaflet of the plasma membrane (IPM) is elevated in all tested APC-truncated CRC cells, driving Wnt-independent formation of Wnt signalosomes through Dishevelled (Dvl)-cholesterol interaction. Cholesterol-Dvl interaction inhibitors potently blocked β-catenin signaling in APC-truncated CRC cells and suppressed their viability. Because of low IPM cholesterol level and low Dvl expression and dependence, normal cells including primary colon epithelial cells were not sensitive to these inhibitors. In vivo testing with a xenograft mouse model showed that our inhibitors effectively suppressed truncated APC-driven tumors without causing intestinal toxicity. Collectively, these results suggest that the most common type of CRC could be effectively and safely treated by blocking the cholesterol-Dvl-β-catenin signaling axis.

Transcription factors, pivotal in gene expression regulation, are essential in cancer progression. Their function is meticulously regulated by post-translational modifications, including ubiquitination. This process, which marks proteins for degradation, can either enhance or inhibit the function of transcription factors, contingent on the context. In cancers, dysregulated ubiquitination of transcription factors contributes to the hallmark of uncontrolled growth and survival of tumors. For example, tumor suppressors such as p53 might be degraded prematurely due to abnormal ubiquitination, causing genomic instability. On the other hand, oncogenic transcription factors may gain stability via ubiquitination, thus facilitating tumorigenesis. Targeting the ubiquitin-proteasome system (UPS) therefore could be a viable therapeutic approach in cancer. Emerging treatments aim to block the ubiquitination of oncogenic transcription factors or to stabilize tumor suppressors. This review underscores the critical impact of transcription factor-altered ubiquitination on cancer progression. Additionally, it outlines innovative therapeutic approaches that involve inhibitors or drugs directed at specific ubiquitin E3 ligases and deubiquitinases (DUBs) that regulate transcription factor activity.

Based on the known Wnt agonist BML-284, we designed and synthesized photoswitchable azo derivative compounds that can act as agonists for the Wnt signaling pathway. These photoswitchable agonists were shown to undergo reversible trans-cis isomerization upon being irradiated with visible light, but only the cis isomer was observed to activate the Wnt signaling pathway, using a luminescense-based reporter assay in cultured cells. One of the compounds, denoted as compound 2, showed ∼88% agonist activity after being subjected to visible light irradiation in comparison to the non-photoswitchable BML-284. We also were able to selectively activate the Wnt signaling pathway using 2 and light irradiation at a specific region of interest in a model cell culture system, highlighting the ability to achieve spatiotemporal regulation.

Systemic sclerosis (SSc) is a prototypic fibrosing disorder characterized by widespread fibrosis and immune dysregulation. Current evidence highlights the intricate cross-talk between the canonical Wnt/β-catenin signaling pathway and transforming growth factor-beta (TGF-β) signaling, both of which play fundamental roles in the pathogenesis of fibrosis. This review aims to elucidate the central role of the Wnt/β-catenin-TGF-β pathway and TGF-β signal transduction pathway in fibrotic diseases, focusing on SSc. We summarized evidence from cellular biology studies, animal model investigations, and clinical observations to provide a comprehensive view of the mechanisms by which these pathways cause pathological fibrosis. In addition, we explore the possibilities of antifibrotic therapeutic strategies against Wnt/β-catenin-TGF-β signaling to counteract fibrosis. We aim to delineate approaches towards effectively treating fibrosis in SSc by targeting these interconnected signaling pathways.

Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer, accounting for 45.3% of all cases and serving as a major cause of cancer-related mortality. Although cisplatin (DDP) is a cornerstone in LUAD therapy, its efficacy is often compromised by resistance, leading to therapeutic failure and poor patient outcomes. Lipid metabolism and associated proteins, such as perilipin 3 (PLIN3), have been increasingly implicated in cancer progression and chemoresistance. However, the precise mechanisms through which PLIN3 contributes to cisplatin (DDP) resistance in LUAD remain poorly understood.

To investigate the role of PLIN3 in DDP resistance, its expression in LUAD tissues and its correlation with patient prognosis were analyzed using bioinformatics databases and validated through clinical sample analysis. The effects of PLIN3 knockdown and overexpression on DDP resistance and Wnt3a/β-catenin signaling were assessed using quantitative real-time PCR (qPCR), western blotting, cytotoxicity assays, and colony formation assays. Bioinformatics screening identified FOS-like antigen 1 (FOSL1) as a transcription factor positively correlated with PLIN3, and its involvement in DDP resistance was further examined both in vitro and in vivo.

PLIN3 expression is significantly elevated in LUAD tissues and correlates with poor overall survival. In LUAD cells, PLIN3 overexpression enhanced DDP resistance by upregulating Wnt3a expression and promoting β-catenin nuclear translocation. Bioinformatics analysis identified FOSL1 as a key transcription factor regulating PLIN3 expression. Experimental validation confirmed that FOSL1 directly binds to the PLIN3 promoter, activating the Wnt3a/β-catenin pathway and promoting DDP resistance. Knockdown of PLIN3 or inhibition of Wnt3a signaling reversed the effects of FOSL1 overexpression on DDP resistance.

This study demonstrates that PLIN3 contributes to DDP resistance in LUAD by activating the Wnt3a/β-catenin signaling pathway, with FOSL1 acting as a critical upstream regulator. Targeting the FOSL1/PLIN3/Wnt/β-catenin axis may provide a promising therapeutic strategy for overcoming chemoresistance in LUAD.

This study explored the expression patterns of epithelial-mesenchymal transition markers E-cadherin and beta-catenin in mild and moderate oral epithelial dysplasia (OED) to determine whether their expression predicts malignant progression in oral tissue.

Formalin-fixed paraffin-embedded tissue specimens with mild or moderate dysplasia were retrieved from 87 patients. Immunohistochemistry was performed to compare E-cadherin and beta-catenin expression in tissue sections that progressed to severe dysplasia, carcinoma in situ, or squamous cell carcinoma (n = 29) with those that did not progress (n = 58). Expression patterns were observed in the basal, parabasal, lower spinous, and upper spinous epithelial layers. Expression was assessed in the cell membrane for E-cadherin and beta-catenin (low expression = absent/weak staining, high = moderate/strong) and in the cytoplasm and nucleus for beta-catenin (low = absence, high = presence). Logistic regression was used to predict progression based on the expression pattern.

There were no significant differences in the progression and expression patterns of E-cadherin and beta-catenin (p > 0.05).

This study found that the expression of E-cadherin and beta-catenin was not a predictor of early malignant progression, highlighting the importance of longitudinal studies in studying progression.

Dentin, a complex, living, and porous mineral substance, is produced by the mineralization of predentin, which is secreted by odontoblasts. This substance is crucial for maintaining the health of teeth. However, the specific function of the vitamin D receptor (Vdr) in the mineralization of odontoblasts, dentin homeostasis, and its interaction with Wnt signaling pathway during dentin apposition is not well understood. In this study, we employed Vdr transgenic knockout mice to study the dental effects and observed enlarged pulp cavities, diminished dentin, and increased predentin thickness in Vdr-/- mice. We further reduced Vdr expression in odontoblasts and analyzed the changes in mineralization and Wnt signaling pathway. Our results showed decreased levels of mineralization and its markers Dspp, Alpl, Opn, Col-1, and Bsp in Vdr-knockdown odontoblasts. Additionally, the Wnt signaling pathway was downregulated, as indicated by lower levels of β-catenin, Lef1, and Axin2, and higher levels of Dkk1. We then attempted to rescue these effects by treating them with lithium chloride (LiCl) which activated the Wnt signaling pathway and appeared to restore the mineralization capacity of odontoblasts. Overall, our findings suggest that Vdr can mediate the Wnt signaling pathway to regulate odontoblasts differentiation during dentin apposition, presenting new potential approaches for improving dental health.

Screening bioactive compounds from natural sources, including animals and plants, is a valuable strategy for identifying novel anti-tumor agents. α-Toxin BmK-M9, a key component of scorpion venom, has received limited attention regarding its potential anti-cancer effects and underlying mechanisms in breast cancer. This study investigates the effects and mechanisms of BmK-M9 in breast cancer using in vitro experiments and a nude mouse model. mRNA sequencing was performed to identify affected signaling pathways, while Western blotting and immunohistochemistry were utilized to analyze the Wnt/β-catenin signaling pathway. The results demonstrated that BmK-M9 significantly inhibited breast cancer cell invasion and migration in vitro and suppressed tumor growth in vivo. Transcriptomic analysis revealed that BmK-M9 influenced cellular processes related to proliferation, apoptosis, motility, and metabolism. Furthermore, BmK-M9 markedly downregulated β-catenin expression in the Wnt/β-catenin pathway. These findings suggest that BmK-M9 exerts anti-tumor effects in breast cancer by modulating Wnt/β-catenin signaling, highlighting its potential as a promising therapeutic candidate.

Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved.

In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets.

We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC.

We uncovered that LINC02418 is essential for cancer cell clonogenic outgrowth. Mechanistically, LINC02418 regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target LINC02418 RNA in vivo.

We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition.

Cancer remains one of the most formidable challenges in the medical field in this century, largely because of its poorly understood pathogenesis. Fortunately, recent advancements in the understanding of cancer pathogenesis have helped identify more therapeutic targets for improved treatment outcomes. The WNT signaling pathways are highly conserved cascades that participate in diverse physiologic processes, such as embryonic development, tissue homeostasis, and tissue regeneration. Ferroptosis, a unique iron-dependent form of cell death that is distinct from apoptosis, is driven by lipid peroxidation and excessive reactive oxygen species production. Emerging evidence shows that the dysregulation of WNT signaling pathways and ferroptosis, as well as their intricate cross-talk, plays crucial roles in cancer progression and therapeutic resistance, indicating their potential as targets for cancer therapies. This review provides a comprehensive overview of the current understanding of the cross-talk between WNT signaling pathways and ferroptosis in the pathogenesis and progression of cancer, with a specific focus on the regulatory role of the canonical WNT cascade in cancer-related ferroptosis. In addition, we discuss the pharmacologic mechanisms of current strategies that inhibit canonical WNT signaling and/or induce ferroptosis in cancer treatment. We propose that combining canonical WNT pathway inhibitors and ferroptosis inducers with current therapies represents a promising therapeutic strategy for personalized cancer treatment.

Development of the multilayered cerebral cortex relies on precise orchestration of neurogenesis, neuronal migration, and differentiation, processes tightly regulated by microtubule dynamics. Mutations in tubulin superfamily genes have been associated with tubulinopathies, encompassing a spectrum of cortical malformations including microcephaly and lissencephaly. Here, we focus on γ-tubulin, a pivotal regulator of microtubule nucleation encoded by TUBG1. We investigate its role in brain development using a zebrafish model with somatic tubg1 mutation, recapitulating features of TUBG1-associated tubulinopathies in patients and mouse disease models. We demonstrate that γ-tubulin deficiency disrupts neurogenesis and brain development, mirroring microcephaly phenotypes. Furthermore, we uncover a novel potential regulatory link between γ-tubulin and canonical Wnt/β-catenin signaling, with γ-tubulin deficiency impairing Wnt activity. Our findings provide insights into the pathogenesis of cortical defects and suggest that γ-tubulin could be a potential target for further research in neurodevelopmental disorders, although challenges such as mode of action, specificity, and potential side effects must be addressed.

AXIN proteins are major components of the β-catenin destruction complex or degradasome, which limits β-catenin nuclear translocation and Wnt signalling activation at steady state. Schmidt et al. performed quantitative analysis of cellular AXIN protein levels in human colorectal cancer cells and revealed that AXIN2 plays a non-redundant role in regulating the total AXIN pool and Wnt/β-catenin signalling activity. Tankyrase (TNKS) inhibitors failed to inhibit Wnt/β-catenin signalling in AXIN2 knockout cells, suggesting that AXIN2 is essential for TNKS inhibitors to function. Mechanistically, the authors show that AXIN2 recruits TNKS to AXIN1 and promotes TNKS-mediated degradation of AXIN1. These findings may have important implications for anti-cancer therapy by TNKS small molecule inhibitors.

Pyroptosis is an important inflammatory form of cell death and Mycobacterium tuberculosis (M.tb) chronic infection triggers excessive inflammatory pyroptosis of macrophages. Our previous research has confirmed that a small compound pyrvinium pamoate (PP) could inhibit inflammatory pathological changes and mycobacterial burden in M.tb-infected mice, but the potential mechanism of PP for inhibiting M.tb-induced inflammation remains unexplored.

The effects of PP on the NLRP3-ASC-Casp1 inflammasome assembly and activation, gasdermin D (GSDMD) mediated pyroptosis and inflammatory cytokines expression were assessed in human THP-1-derived macrophages after M.tb H37Rv/H37Ra/ Salmonella typhimurium (S. typhimurium) infection or LPS treatment by Transcriptome sequencing, RT-qPCR, Co-immunoprecipitation and Western Blot (WB) analysis. The lactate dehydrogenase (LDH) release assay was used to evaluate the CC50 of PP in M.tb-infected THP-1 cells.

We found that M.tb/S. typhimurium infection and LPS treatment significantly activate NLRP3-ASC-Casp1 inflammasome activation, GSDMD-mediated pyroptosis and inflammatory cytokines (IL-1β and IL-18) expression in macrophages, whereas PP could suppress these inflammatory effects in a dose dependent manner. Regarding the PP-inhibition mechanism, we further found that this inhibitory activity is mediated through the PP-targeting casein kinase 1A1 (CK1α)-β-catenin-NF-κB pathway and CK1α-NRF2-mitochondrial oxidative phosphorylation (OXPHOS) pathway. In addition, a CK1α specific inhibitor D4476 or CK1α siRNA could reverse these inhibitory effects of PP on bacteria-induced inflammatory responses in macrophages.

This study reveals a previously unreported mechanism that pyrvinium can inhibit NLRP3 inflammasome and GSDMD-IL-1β inflammatory pyroptosis via targeting suppressing CK1α-β-catenin-NF-κB and CK1α-NRF2-mitochondrial OXPHOS pathways, suggesting that pyrvinium pamoate holds great promise as a host directed therapy (HDT) drug for mycobacterial-induced excessive inflammatory response.

Testis-specific transcript 10 (Tex10) is highly expressed in the testis, embryonic stem cells (ESCs), and primordial germ cells (PGCs). We previously generated a Tex10 knockout mouse model demonstrating its critical roles in ESC pluripotency and preimplantation development. Here, using conditional knockout mice and dTAG-degron ESCs, we show Tex10 is required for spermatogenesis and ESC-to-PGCLC differentiation. Specifically, Tex10-null spermatocytes arrest at metaphase I, compromising round spermatid formation. Tex10 depletion and overexpression compromise and enhance ESC-to-PGCLC differentiation, respectively. Mechanistically, bulk and single-cell RNA sequencing reveals that Tex10 depletion downregulates genes involved in pluripotency, PGC development, and spermatogenesis while upregulating genes promoting somatic programs. Chromatin occupancy study reveals that Tex10 binds to H3K4me3-marked promoters of Psmd3 and Psmd7, negative regulators of Wnt signaling, and activates their expression, thereby restraining Wnt signaling. Our study identifies Tex10 as a previously unappreciated factor in spermatogenesis and PGC development, offering potential therapeutic insights for treating male infertility.

Epigenetic modifications of chromatin are essential for the establishment of cell identities during embryogenesis. Between embryonic days 3.5-7.5 of murine development, major cell lineage decisions are made that discriminate extraembryonic and embryonic tissues, and the embryonic primary germ layers are formed, thereby laying down the basic body plan. In this review, we cover the contribution of dynamic chromatin modifications by DNA methylation, changes of chromatin accessibility, and histone modifications, that in combination with transcription factors control gene expression programs of different cell types. We highlight the differences in regulation of enhancer and promoter marks and discuss their requirement in cell lineage specification. Importantly, in many cases, lineage-specific targeting of epigenetic modifiers is carried out by pioneer or master transcription factors, that in sum mediate the chromatin landscape and thereby control the transcription of cell-type-specific gene programs and thus, cell identities.

The stria vascularis (SV) is an essential component of the inner ear that regulates the ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding of the SV, and consequently therapeutic availability for SV degeneration, is lacking. We developed a whole-tissue explant model from neonatal and mature mice to create a platform for advancing SV research. We validated our model by demonstrating that the proliferative behavior of the SV in vitro mimics SV in vivo. We also provided evidence for pharmacological experimentation by investigating the role of Wnt/β-catenin signaling in SV proliferation. Finally, we performed single-cell RNA sequencing from in vivo neonatal and mature mouse SV and surrounding tissue and revealed key genes and pathways that may play a role in SV proliferation and maintenance. Together, our results contribute new insights into investigating biological solutions for SV-associated hearing loss.

Evolutionarily, Wnt/β-catenin signaling is well-conserved and supports several key cell-biological processes (e.g. adhesion and proliferation). Its crucial component, β-catenin, has been described in several organisms, however, its identification and characterization are notably lacking in annelid earthworms. Here, we report a novel β-catenin homologue from the earthworm Eisenia andrei, termed Ea-β-catenin. The full-length 3253 nt Ea-β-catenin mRNA includes an open reading frame of 2499 nt encoding a putative protein with 833 amino acid residues that comprise 11 classical armadillo-repeat regions. Phylogenetic analysis indicates that Ea-β-catenin shows strong homology with Lophotrochozoan β-catenins. Ubiquitous, but variable expressions of Ea-β-catenin were observed in distinct earthworm tissues. During embryogenesis, Ea-β-catenin mRNA gradually increased from the E1 to E4 developmental stages. Regeneration experiments revealed an inverse correlation between Ea-β-catenin mRNA levels and the rate of EdU+/PY489-β-catenin+ proliferating cells during the second week of the posterior blastema formation. In vitro exposures to poly(I:C) and zymosan significantly increased Ea-β-catenin mRNA levels, while small molecule Wnt-pathway modulators such as LiCl or iCRT14 increased or decreased Ea-β-catenin mRNA expression, and nuclear translocation of PY489-β-catenin, respectively. These novel results pave the way for follow-up studies aimed at characterizing additional members of the Wnt/β-catenin pathway that may be involved in embryonic and/or postembryonic development, as well as innate immunity in earthworms.

Most wounds form scars without hair follicles. However, in the wound-induced hair neogenesis (WIHN) model of skin regeneration, wounds regenerate hair follicles if tissue rigidity is optimal. Although WIHN depends on Wnt signaling, whether Wnt performs a mechanoregulatory role that contributes to regeneration remains uncharacterized. Here, we demonstrate that Wnt signaling affects mechanosensitivity at both cellular and tissue levels to drive WIHN. Atomic force microscopy revealed an attenuated substrate rigidity response in epidermal but not dermal cells of healing wounds. Super-resolution microscopy and nanoneedle probing of intracellular compartments in live human keratinocytes revealed that Wnt-induced chromatin remodeling triggers a 10-fold drop in nuclear rigidity without jeopardizing the nucleocytoskeletal mechanical coupling. Mechanistically, Wnt signaling orchestrated a massive reorganization of actin architecture and recruited adherens junctions to generate a mechanical syncytium-a cohesive contractile unit with superior capacity for force coordination and collective durotaxis. Collectively, our findings unveil Wnt signaling's mechanoregulatory role that manipulates the machinery of mechanotransduction to drive regeneration.

During gastrulation, Wnt-β-catenin signaling dictates lineage bifurcation generating different mesoderm cell types. However, the specific role of Wnt receptors in mesoderm specification remains elusive. Using selective Frizzled (FZD) and LRP5/6 antibody-based agonists, we examined FZD receptors' function during directed mesoderm differentiation of human pluripotent stem cells (hPSCs). We found that FZD2 and FZD7 receptors are expressed at the membrane of hPSCs and that their activation triggers β-catenin signaling with different kinetics, thereby influencing mesoderm patterning choices. Specifically, FZD7 activation enhances both paraxial and lateral mesoderm differentiation, whereas FZD2 activation favors paraxial mesoderm. Mechanistically, FZD2 activation promotes sustained Wnt-β-catenin levels, guiding hPSCs differentiation toward paraxial mesoderm, while blocking lateral mesoderm. In contrast, FZD7 activation kinetics display similar initial activation but more dampening of β-catenin signaling, permitting lateral mesoderm induction in addition to paraxial mesoderm specification. Our findings reveal non-redundant roles for FZD2 and FZD7 in mesoderm specification, offering leverage for precise directed differentiation outcomes.

To elucidate the anti-ageing mechanism of the combination of eight ingredients on the skin from a multidimensional view of the skin.

The target pathway mechanisms of composition to delay skin ageing were investigated by a network pharmacology approach and experimentally validated at three levels: epidermal, dermal, and tissue.

We identified 24 statistically significant skin ageing-related pathways, encompassing crucial processes such as epidermal barrier repair, dermal collagen and elastin production, inhibition of reactive oxygen species (ROS), as well as modulation of acetylcholine and acetylcholine receptor binding. Furthermore, our in vitro experimental findings exhibited the following outcomes: the composition promotes fibroblast proliferation and the expression of barrier-related genes in the epidermis; it also stimulated the expression of collagen I, collagen III, and elastic fibre while inhibiting ROS and β-Gal levels in HDF cells within the dermis. Additionally, Spilanthol in the Acmella oleracea extract contained in the composition demonstrated neuro-relaxing activity in Zebrafish embryo, suggesting its potential as an anti-wrinkle ingredient at the hypodermis level.

In vitro experiments validated the anti-ageing mechanism of composition at multiple skin levels. This framework can be extended to unravel the functional mechanisms of other clinically validated compositions, including traditional folk recipes utilized in cosmeceuticals.

Wnt signaling is essential for cell growth and tumor formation and is abnormally activated in colorectal cancer (CRC), contributing to tumor progression; however, the specific role and regulatory mechanisms involved in tumor development remain unclear. Here, we show that Ephexin1, a guanine nucleotide exchange factor, is significantly overexpressed in CRC and is correlated with increased Wnt/β-catenin pathway activity. Through comprehensive analysis, including RNA sequencing data from TCGA and functional assays, we observed that Ephexin1 promotes tumor proliferation and migration by activating the Wnt/β-catenin pathway. This effect was mediated by the interaction of Ephexin1 with Axin1, a critical component of the β-catenin destruction complex, which in turn enhanced the stability and activity of β-catenin in signaling pathways critical for tumor development. Importantly, our findings also suggest that targeting Ephexin1 may increase the efficacy of Wnt/β-catenin pathway inhibitors in CRC treatment. These findings highlight the potential of targeting Ephexin1 as a strategy for developing effective treatments for CRC, suggesting a novel and promising approach to therapy aimed at inhibiting cancer progression.

Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades.

Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, < 50 years) compared to late-onset (LOCRC, ≥ 50 years).

EOCRC was associated with a higher prevalence of Asian and Hispanic patients, rectal or left-sided tumors (72% vs. 59%), and advanced-stage disease. Molecular analyses revealed differences in mutation patterns, with EOCRC having higher frequencies of TP53 (74% vs. 68%, p < 0.01) and SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p < 0.001) and NOTCH1 (2.7% vs. 4.1%, p = 0.01) mutations were more prevalent in LOCRC. Stratification by tumor site and MSI status highlighted significant location- and age-specific molecular differences, such as increased KRAS and CTNNB1 mutations in right-sided EOCRC and higher BRAF prevalence in MSI-H LOCRC (47% vs. 6.7%, p < 0.001). Additionally, co-occurrence analysis revealed unique mutational networks in EOCRC MSS, including significant co-occurrences of FBXW7 with NOTCH3, RB1, and PIK3R1.

This study highlights the significance of age-specific molecular profiling, offering insights into the unique biology of EOCRC and potential clinical applications.

Diabetic periodontitis (DP) is a commonly co-occurring complication in diabetes patients characterized by advanced gum disease and bone resorption. Conventional treatment modalities often fail to adequately address the underlying biological disruptions caused by diabetes. The use of traditional medicinal formulas Kouqiangjie Formula (KQJF) potentially offers novel therapeutic approaches for DP, but its detailed regulatory mechanisms remain unclear.

This study aims to investigate the impacts of KQJF on osteoblastic activity and inflammatory responses in a rat model and in vitro pre-osteoblast cultures under conditions mimicking DP, focusing on the involvement of the miR-29a-3p-Dkk-1/Wnt/β-catenin signaling pathway.

Using network pharmacological analysis, micro-CT, histological staining, and an array of molecular biology methodologies including Western blotting, RT-qPCR, and immunofluorescence, we investigated the systemic and cellular responses to KQJF treatment. Both in vivo (rat model) and in vitro (MC3T3-E1 pre-osteoblasts) models subjected to high glucose and lipopolysaccharide (HG + LPS) stress were used to simulate DP conditions.

Network pharmacological analyses, incorporating protein-protein interactions and pathway enrichment, disclosed that KQJF interacts with pathways crucial for inflammation and bone metabolism. Experimentally, KQJF significantly preserved alveolar bone architecture, reduced osteoclast activity, and dampened inflammatory cytokine production in DP rats. In pre-osteoblasts, KQJF enhanced cell viability, promoted cell cycle progression, and decreased apoptosis. At the molecular level, KQJF treatment upregulated miR-29a-3p and downregulated Dkk-1, thereby activating the Wnt/β-catenin pathway. The interventional studies with miR-29a-3p antagonists and Dkk-1 knockdown further confirmed the regulatory role of the miR-29a-3p/Dkk-1 axis in mediating the effects of KQJF.

KQJF mitigates the deleterious effects of DP by enhancing osteoblastic activity and reducing inflammatory responses, predominantly through the modulation of the miR-29a-3p-Dkk-1/Wnt/β-catenin signaling pathway. These discoveries underscore the therapeutic promise of KQJF in managing bone and inflammatory complications of DP, offering insights into its mechanism, and supporting its use in clinical settings.

YAP/TAZ (Yes-associated protein/paralog transcriptional co-activator with PDZ-binding domain) are transcriptional cofactors that are the key and major downstream effectors of the Hippo signaling pathway. Both are known to play a crucial role in defining cellular outcomes, including cell differentiation, cell proliferation, and apoptosis. Aside from the canonical Hippo signaling cascade with the key components MST1/2 (mammalian STE20-like kinase 1/2), SAV1 (Salvador homologue 1), MOB1A/B (Mps one binder kinase activator 1A/B) and LATS1/2 (large tumor suppressor kinase 1/2) upstream of YAP/TAZ, YAP/TAZ activation is also influenced by numerous other signaling pathways. Such non-canonical regulation of YAP/TAZ includes well-known growth factor signaling pathways such as the epidermal growth factor receptor (EGFR)/ErbB family, Notch, and Wnt signaling as well as cell-cell adhesion, cell-matrix interactions and mechanical cues from a cell's microenvironment. This puts YAP/TAZ at the center of a complex signaling network capable of regulating developmental processes and tissue regeneration. On the other hand, dysregulation of YAP/TAZ signaling has been implicated in numerous diseases including various cancers and neurodevelopmental disorders. Indeed, in recent years, parallels between cancer development and neurodevelopmental disorders have become apparent with YAP/TAZ signaling being one of these pathways. This review discusses the role of YAP/TAZ in brain development, cancer and neurodevelopmental disorders with a special focus on the interconnection in the role of YAP/TAZ in these different conditions.

In multicellular organisms, Wnt proteins govern stem and progenitor cell renewal and differentiation to regulate embryonic development, adult tissue homeostasis and tissue regeneration. Defects in canonical Wnt signalling, which is transduced intracellularly by β-catenin, have been associated with developmental disorders, degenerative diseases and cancers. Although a simple model describing Wnt-β-catenin signalling is widely used to introduce this pathway and has largely remained unchanged over the past 30 years, in this Review we discuss recent studies that have provided important new insights into the mechanisms of Wnt production, receptor activation and intracellular signalling that advance our understanding of the molecular mechanisms that underlie this important cell-cell communication system. In addition, we review the recent development of molecules capable of activating the Wnt-β-catenin pathway with selectivity in vitro and in vivo that is enabling new lines of study to pave the way for the development of Wnt therapies for the treatment of human diseases.

The Wnt signaling pathway is critical in the onset and progression of gastrointestinal (GI) cancers. Anomalies in this pathway, often stemming from mutations in critical components such as adenomatous polyposis coli (APC) or β-catenin, lead to uncontrolled cell proliferation and survival. In the case of colorectal cancer, dysregulation of the Wnt pathway drives tumor initiation and growth. Similarly, aberrant Wnt signaling contributes to tumor development, metastasis, and resistance to therapy in other GI cancers, such as gastric, pancreatic, and hepatocellular carcinomas. Targeting the Wnt pathway or its downstream effectors has emerged as a promising therapeutic strategy for combating these highly aggressive GI malignancies. Here, we review the dysregulation of the Wnt signaling pathway in the pathogenesis of GI cancers and further explore the therapeutic potential of targeting the various components of the Wnt pathway. Furthermore, we summarize and integrate the preclinical evidence supporting the therapeutic efficacy of potent Wnt pathway inhibitors with completed and ongoing clinical trials in GI cancers. Additionally, we discuss the challenges of Wnt pathway-targeted therapies in GI cancers to overcome these concerns for effective clinical translation.

Copper (Cu) is a global environmental pollutant that poses a serious threat to humans and ecosystems. Copper induces developmental neurotoxicity, but the underlying molecular mechanisms are unknown. Neurons are nonrenewable, and they are unable to mitigate the excessive accumulation of pathological proteins and organelles in cells, which can be ameliorated by autophagic degradation. In this study, we established an in vitro model of Cu2+-exposed (0, 15, 30, 60 and 120 μM) SH-SY5Y cells to explore the role of autophagy in copper-induced developmental neurotoxicity. The results showed that copper resulted in the reduction and shortening of neural synapses in differentiated cultured SH-SY5Y cells, a downregulated Wnt signaling pathway, and nuclear translocation of β-catenin. Exposure to Cu2+ increased autophagosome accumulation and autophagic flux blockage in terms of increased sequestosome 1 (p62/SQSTM1) and microtubule-associated protein 1 light chain 3B (LC3B) II/LC3BI expressions and inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway. Furthermore, copper induced apoptosis, characterized by increased expressions of Bcl2 X protein (Bax), caspase 3, and Poly (ADP-ribose) polymerase (PARP) and decreased expression of B-cell lymphoma 2 (Bcl2). Compared with the 120 μM Cu2+ exposure group alone, autophagy activator rapamycin pretreatment increased expression of Wnt and β-catenin nuclear translocation, decreased expression of LC3BII/LC3BI and p62, as well as upregulated expression of Bcl2 and downregulated expressions of caspase 3 and PARP. In contrast, after autophagy inhibitor chloroquine pretreatment, expressions of Wnt and β-catenin nuclear translocation were decreased, expression levels of LC3BII/LC3BI and p62 were upregulated, expression of Bcl2 was decreased, while expression levels of caspase 3, Bax, and PARP were increased. In conclusion, the study demonstrated that autophagosome accumulation and autophagic flux blockage were associated with copper-induced developmental neurotoxicity via the Wnt signaling pathway, which might deepen the understanding of the developmental neurotoxicity mechanism of environmental copper exposure.

Static magnetic field (SMF) as an effective physical stimulus is capable of osteogenic differentiation for multiple mesenchymal stem cells, including human periodontal ligament stem cells (hPDLSCs). However, the exact molecular mechanism is still unknown. Therefore, this study intends to excavate molecular mechanisms related to SMF in hPDLSCs using functional experiments.

hPDLSCs were treated with different intensities of SMF, H19 lentivirus, and Wnt/β-catenin pathway inhibitor (XAV939). Changes in osteogenic markers (Runx2, Col Ⅰ, and BMP2), Wnt/β-catenin markers (β-catenin and GSK-3β), and calcified nodules were examined using RT-qPCR, western blotting, and alizarin red staining in hPDLSCs.

SMF upregulated the expression of H19, and SMF and overexpressing H19 facilitated the expression of osteogenic markers (Runx2, Col Ⅰ, and BMP2), activation of the Wnt/β-catenin pathway, and mineralized sediment in hPDLSCs. Knockdown of H19 alleviated SMF function, and treatment with XAV939 limited SMF- and H19-mediated osteogenic differentiation of hPDLSCs. Notably, the expression of hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p in hPDLSCs was regulated by SMF, and may form an endogenous competitive RNA mechanism with H19 and β-catenin.

SMF contributes to the osteogenic differentiation of hPDLSCs by mediating the H19/Wnt/β-catenin pathway, and hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p may be the key factors in it.

In neurons, the acquisition of a polarized morphology is achieved upon the outgrowth of a single axon from one of several neurites. Small extracellular vesicles (sEVs), such as exosomes, from diverse sources are known to promote neurite outgrowth and thus may have therapeutic potential. However, the effect of fibroblast-derived exosomes on axon elongation in neurons of the central nervous system under growth-permissive conditions remains unclear. Here, we show that fibroblast-derived sEVs promote axon outgrowth and a polarized neuronal morphology in mouse primary embryonic cortical neurons. Mechanistically, we demonstrate that the sEV-induced increase in axon outgrowth requires endogenous Wnts and core PCP components including Prickle, Vangl, Frizzled, and Dishevelled. We demonstrate that sEVs are internalized by neurons, colocalize with Wnt7b, and induce relocalization of Vangl2 to the distal axon during axon outgrowth. In contrast, sEVs derived from neurons or astrocytes do not promote axon outgrowth, while sEVs from activated astrocytes inhibit elongation. Thus, our data reveal that fibroblast-derived sEVs promote axon elongation through the Wnt-PCP pathway in a manner that is dependent on endogenous Wnts.

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed through the condensation of proteins, nucleic acids, and other molecules-in driving efficient and dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression and intracellular signal transduction, enabling rapid and finely tuned cellular responses. Their ability to regulate cellular signaling pathways is particularly significant, as it requires a careful balance between flexibility and precision. Disruption of this balance can lead to pathological conditions, including neurodegenerative diseases, cancer, and viral infections. Consequently, biomolecular condensates have emerged as promising therapeutic targets, with the potential to offer novel approaches to disease treatment. In this review, we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways, their roles in health and disease, and potential strategies for modulating condensate dynamics as a therapeutic approach. Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.

Cancer represents an intricate and heterogeneous ailment that evolves from a multitude of epigenetic and genetic variations that disrupt normal cellular function. The WNT/β-catenin pathway is essential in maintaining the balance between cell renewal and differentiation in various tissues. Abnormal activation of this pathway can lead to uncontrolled cell growth and initiate cancer across a variety of tissues such as the colon, skin, liver, and ovary. It enhances characteristics that lead to cancer progression, including angiogenesis, invasion and metastasis. Processes like autophagy and apoptosis which regulate cell death and play a crucial role in maintaining cellular equilibrium are also intimately linked with WNT/ β-catenin pathway. Thus, targeting WNT pathway has become a key strategy in developing antitumor therapies. Employing small molecule inhibitors has emerged as a targeted therapy to improve the clinical outcome compared to conventional cancer treatments. Many strategies using small molecule inhibitors for modulating the WNT/β-catenin pathway, such as hindering WNT ligands' secretion or interaction, disrupting receptor complex, and blocking the nuclear translocation of β-catenin have been investigated. These interventions have shown promise in both preclinical and clinical settings. This review provides a comprehensive understanding of the role of WNT/β-catenin signalling pathway's role in cancer, emphasizing its regulation of autophagy and apoptosis. Our goal is to highlight the potential of specific small molecule inhibitors targeting this pathway, fostering the development of novel, tailored cancer treatments.

WNT/β-catenin signaling plays key roles in development and cancer1,2. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 and ZNRF3/RNF43 enhances WNT/β-catenin signaling3-5. Here, we elucidate the overall landscape of architectures in multiple LGR4, RSPO2, and ZNRF3 assemblies, showcasing varying stoichiometries and arrangements. These structures reveal that LGR4 and RSPO2 capture distinct states of ZNRF3. The intrinsic heterogeneity of the LGR4-RSPO2-ZNRF3 assembly is influenced by LGR4 content. Particularly, in the assembly complex with a 2:2:2 ratio, two LGR4 protomers induce and stabilize the inactive state of ZNRF3, characterized by a wide inward-open conformation of two transmembrane helices (TM helices). This specific assembly promotes a stable complex, facilitating LGR4-induced endocytosis of ZNRF3. In contrast, the active dimeric ZNRF3, bound by a single LGR4, adopts a coiled-coil TM helices conformation and dimerization of RING domains. Our findings unveil how LGR4 content mediates diverse assemblies, leading to conformational rearrangements in ZNRF3 to regulate WNT/β-catenin signaling, and provide a structural foundation for drug development targeting Wnt-driven cancers.

MAFB is essential for regulating male-type urethral differentiation, and especially, its variation can contribute to hypospadias in mice. However, the potential mechanism is still unclear. Here we observed that the basic leucine zipper (bZIP) transcription factor MAFB and CCAAT/enhancer-binding protein alpha (CEBPA) could promote human urothelium SV-HUC-1 growth. Moreover, MAFB and CEBPA expression were reduced in the prepuce tissues of hypospadias patients. Based on transcriptome sequencing analysis and Western blot, MAFB knockdown was found to suppress CEBPA protein expression and repress Wnt/β-catenin signaling in urothelium cells. Meanwhile, we observed blocked cell-cycle progression from the G1 to the S phase, inhibited cell proliferation, and activated apoptosis. Furthermore, MAFB could facilitate CEBPA transcription and regulate the proliferation of urothelium. The above results indicated that MAFB-mediated inhibition of urothelial SV-HUC-1 growth resulted from inhibiting the Wnt/β-catenin signaling pathway by down-regulating CEBPA. Our findings provide new insight into the understanding of genes associated with hypospadias and the pathogenic mechanism of this disorder.

The Wnt/β-catenin signaling pathway plays a pivotal role in the development, maintenance, and repair of the central nervous system (CNS). This chapter explores the diverse functions of Wnt/β-catenin signaling, from its critical involvement in embryonic CNS development to its reparative and plasticity-inducing roles in response to CNS injury. We discuss how Wnt/β-catenin signaling influences various CNS cell types-astrocytes, microglia, neurons, and oligodendrocytes-each contributing to repair and plasticity after injury. The chapter also addresses the pathway's involvement in CNS disorders such as Alzheimer's and Parkinson's diseases, psychiatric disorders, and traumatic brain injury (TBI), highlighting potential Wnt-based therapeutic approaches. Lastly, zebrafish are presented as a promising model organism for studying CNS regeneration and neurodegenerative diseases, offering insights into future research and therapeutic development.