Search Results (1,263)

RNA-binding proteins (RBPs) play a pivotal role in post-transcriptional gene regulation, influencing various cellular processes, including development, differentiation, and disease progression. Emerging evidence suggests that RBPs function as critical modulators of the canonical Wnt signaling pathway, a key regulator of cell fate determination, proliferation, and tumorigenesis. By controlling the stability, localization, and translation of Wnt pathway components, RBPs fine-tune the dynamic signaling responses necessary for maintaining cellular homeostasis. Several RBPs have been identified as direct regulators of key components in the Wnt cascade, such as IGF2BP1, HuR, and MSI1, impacting their expression and activity. Dysregulation of these RBPs has been linked to aberrant Wnt signaling, contributing to various pathological conditions such as cancers or developmental disorders. This review explores the emerging landscape of RBPs in the regulation of canonical Wnt signaling, highlighting their molecular mechanism, functional implications, and potential as therapeutic targets in Wnt-driven disease. Full article

The next frontier in postmenopausal osteoporosis management lies not in novel pharmacological agents, but in the systematic integration of mechanism-guided drug selection, fall prevention, and long-term adherence strategies into a unified patient-centered care model. This review is intended for clinicians and clinical researchers involved in the diagnosis, treatment, and long-term management of postmenopausal osteoporosis. We provide a mechanism-to-practice framework that explicitly maps each therapeutic class to the specific molecular pathway it targets: bisphosphonates inhibit osteoclast function downstream of RANKL activation; denosumab blocks RANKL directly at the cytokine level; romosozumab inhibits sclerostin to restore Wnt-mediated bone formation. This mechanistic foundation supports a risk-stratified treatment paradigm in which antiresorptives address accelerated remodeling in moderate-risk patients, while patients at very high fracture risk—characterized by severe bone deficit or recent fragility fractures—benefit from an anabolic-first approach followed by consolidation. Beyond drug selection, we examine the persistent treatment gap in which fewer than 20% of post-fracture patients receive therapy, arguing that fall prevention—responsible for >90% of hip fractures—and medication adherence deserve equal priority in clinical practice. We further analyze key controversies, including T-score- versus FRAX-based intervention thresholds, limitations of the trabecular bone score, cost-effectiveness constraints on anabolic-first sequencing, and evidence gaps in post-denosumab transition strategies. By synthesizing mechanistic insights, guideline recommendations, and critical appraisal of current limitations, this review offers not only an overview of existing knowledge but a coherent decision-support model aimed at improving fracture prevention through comprehensive, individualized care. Full article

Obesity and air pollution are two pervasive and increasingly prevalent risk factors for neurodegenerative diseases, like Alzheimer’s disease. Both independently disrupt brain homeostasis through overlapping mechanisms, including chronic neuroinflammation, oxidative stress, and insulin resistance. Recent evidence highlights the Wnt/β-catenin signaling pathway as a critical integrator of these insults, mediating neuroprotective processes such as synaptic plasticity, blood–brain barrier integrity, and neuronal survival. In this review, we synthesize emerging data on how obesity-driven metabolic dysfunction and air pollution-induced oxidative injury synergize to impair brain metabolism and accelerate cognitive decline. We describe the roles of pathways such as JAK-STAT, NF-κB, and TLR4 signaling cascades, as well as leptin and adiponectin imbalances, in modulating glial reactivity and neuroimmune signaling. Particular attention is given to the suppression of Wnt/β-catenin signaling in obese and pollution-exposed brains, and its consequences for Alzheimer’s disease pathology, including β-amyloid accumulation and tau hyperphosphorylation. Finally, we examine the translational implications, highlighting the Wnt pathway as a potential therapeutic target that offers neuroprotection in the context of dual metabolic and environmental stress. Together, these insights provide a mechanistic framework that links systemic dysfunction to central nervous system vulnerability, offering pathways for intervention in at-risk populations. Full article

Background/Objectives: To explore the protective effects of 7-Ketolithocholic acid (7-KLCA) against renal fibrosis and its mechanism, focusing on its interaction with farnesoid X receptor (FXR). Methods: In vitro, TGF-β-induced fibrosis in HK-2/NRK-49F cells and LPS-induced inflammation in HK-2 cells were detected by CCK-8, Western blot, and qPCR. In vivo, unilateral ureteral obstruction (UUO) and adenine (Ade)-induced mouse models were treated with a low/high-dose 7-KLCA or losartan. Renal injury was evaluated via H&E/Masson staining, serum creatinine (SCR), and blood urea nitrogen (BUN) levels. The 7-KLCA-FXR interaction was verified by molecular docking, CETSA, and DARTS. FXR downstream genes and related proteins were measured by WB and qPCR. Results: 7-KLCA inhibited the expression of fibrotic proteins (fibronectin, collagen-I) and reduced the LPS-induced release of inflammatory factors (IL-1β, IL-6). In mice, it alleviated renal swelling, collagen deposition, and tubular damage, while lowering serum SCR and BUN levels. Mechanistically, 7-KLCA stably bound to the FXR ligand-binding domain, enhanced its thermal stability and degradation resistance. It upregulated FXR and its downstream genes SHP and FGF15, thereby inhibiting the activation of TGF-β/Smad and Wnt/β-catenin pathways. Conclusions: This is the first study to clarify the molecular mechanism through which 7-KLCA targets FXR and dually suppresses the key pro-fibrotic pathways TGF-β/Smad and Wnt/β-catenin, thereby exerting anti-renal fibrosis effects. Full article

Age-associated hair loss is primarily driven by decreased function and proliferation of hair follicle stem cells (HFSCs), often exacerbated by increased inhibitory signaling and changes in the stem cell niche. Macrophage polarization to the anti-inflammatory M2 phenotype is known to increase stem cell proliferation. We investigated the effects of poly-D,L-lactic acid (PDLLA) on hair growth in middle-aged skin, focusing on its role in modulating macrophage polarization and HFSC activity. Senescent macrophages were analyzed for Piezo1 activity, macrophage polarization, and secretion of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) after PDLLA treatment. Downstream effects on HFSC proliferation, stemness, and Wnt signaling were assessed, including inhibition experiments using the Piezo1 blocker GsMTx4. In vivo analyses assessed hair follicle number, diameter, length, anagen duration, and hair coverage following PDLLA administration in middle-aged mice. PDLLA increased Piezo1 expression and activity in senescent macrophages, enhancing M2 polarization and secretion of HGF and IGF-1. This activated the RAS/ERK signaling pathway, promoting HFSC proliferation and stemness. Furthermore, PDLLA upregulated Wnt signaling molecules (Wnt3a, Wnt10b, and β-catenin) and anagen phase-related factor (Axin2, LEF1, and Lgr5), which were decreased by GsMTX4. In middle-aged animal skin, PDLLA administration led to increased hair follicle number, diameter, and length, as well as prolonged anagen and greater hair coverage. Collectively, these findings suggest that PDLLA rejuvenates the middle-aged skin microenvironment, at least in part through Piezo1-associated M2 macrophage polarization and enhanced HFSC function, offering a promising therapeutic strategy for age-related hair loss targeting both the immune and the stem cell compartments. Full article

Background: Radiation-induced pulmonary fibrosis (RPF) remains a major burden of successful lung cancer radiotherapy. Clinically validated drugs targeting RPF remains scarce. Methods: We employed a transcriptome-based drug repurposing approach using REMEDY, a computational platform built on the Library of Integrated Network-Based Cellular Signatures (LINCS). Differentially expressed genes (DEGs) derived from radiation-induced lung injury (RILI) models were used as a query to identify compounds capable of reversing pro-fibrotic expression profile. Among top-ranked candidates, homoharringtonine (HHT), an FDA-approved protein synthesis inhibitor, was selected for experimental validation. Anti-fibrotic effects of HHT were assessed using an optimized in vitro fibrotic model based on activation of MRC-5 human lung fibroblasts. Complementary in silico molecular docking analyses were also conducted to explore the mechanistic basis of HHT’s actions. This represents the first transcriptome-guided, LINCS-based drug repurposing study applied specifically to radiation-induced pulmonary fibrosis, utilizing RPF-derived molecular signatures rather than general fibrosis-related datasets. Results: HHT significantly attenuated key fibrotic phenotypes, including fibroblast proliferation, myofibroblast differentiation, and extracellular matrix (ECM) production. Notably, HHT suppressed expression of cyclin D1 and α-smooth muscle actin (α-SMA), and reduced collagen deposition. Mechanistic investigations revealed that HHT modulates two pro-fibrotic pathways: RhoA/ROCK and Wnt/β-catenin signaling. Molecular docking further suggested that HHT may directly interact with fibrosis-related receptors such as integrins and Frizzled, providing structural insight into its anti-fibrotic potential. These findings underscore the novelty of reassigning HHT to a radiation-specific fibrotic context using a signature-reversal strategy uniquely tailored to RPF biology. Conclusions: Our findings identify HHT as a promising treatment of RPF, offering a dual mechanism of action—interruption of protein synthesis and targeted inhibition of fibrotic signaling pathways. This study highlights the value of computational drug repurposing platforms for accelerating therapeutic discovery. Further preclinical investigations are warranted to evaluate HHT’s in vivo efficacy and clinical applicability in RPF. Full article

Background: Loneliness (LON) is a heritable psychosocial trait that frequently co-occurs with major depressive disorder (MDD) and sleep traits. Despite known genetic contributions, the shared genetic architecture and molecular mechanisms underlying their co-occurrence remain largely unknown. This study aimed to uncover novel genetic risk loci and cross-trait gene expression effects. Methods: Large-scale genome-wide association study (GWAS) datasets were analyzed using the causal mixture model (MiXeR) to estimate polygenicity and shared genetic architecture. Genetic correlation analyses were performed using linkage disequilibrium score regression (LDSC) and local analysis of [co]variant annotation (LAVA). Conditional and conjunctional FDR methods further identified single nucleotide polymorphisms (SNPs). FUMA was used for gene mapping and annotation, and transcriptome-wide association studies (TWAS) assessed cross-trait gene expression effects. Results: Analyses revealed extensive polygenic overlap between LON, MDD, and sleep-related traits, with concordant and discordant effects. Several novel loci were identified, and cross-trait gene expression effects were observed in multiple brain-expressed genes, including WNT3, ARHGAP27, PLEKHM1, and FOXP2. These findings provide insight into the shared genetic architecture and relevance of these traits. Conclusions: This study demonstrates a significant shared polygenic architecture among LON, MDD, and sleep traits, providing new biological insights. It advances our understanding of cross-trait genetic mechanisms and identifies potential targets for future research, offering broader implications for trait co-occurrence. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington’s Disease (HD), share pathologic mechanisms including oxidative stress, mitochondrial dysfunction, and protein aggregation. However, they differ in age of onset and clinical progression. Emerging evidence highlights primary cilia (PC) as a key regulator of neuronal aging and the progression of these diseases. Dysfunctional PC may impair key signaling pathways, such as Sonic Hedgehog (Shh) and Wnt, promote oxidative stress, mitochondrial damage, and epigenetic instability. PC may also influence intercellular communication by regulating the biogenesis of exosomes and modulating tunneling nanotube (TNT) formation, both of which propagate toxic proteins between neurons. Mechanistically, the regulation of ciliary length is disrupted in AD, which leads to ciliary dysfunction that interferes with signaling pathways and promotes the aggregation of amyloid-beta. This amyloid-beta is then propagated through TNTs and exosomes, spreading neuronal damage. In PD, the accumulation of alpha-synuclein (α-syn) also impairs cilia function, thereby compromising the cell’s response to oxidative stress. This results in the formation of abnormal TNTs and defective exosome-mediated clearance, ultimately contributing to neurodegeneration. Similarly, the mutant huntingtin protein aggregates within primary cilia in HD, morphologically disrupting them by obstructing intraflagellar transport. Damaged cilia are also associated with increased TNT formation and the exosomal release of toxic proteins, which leads to mitochondrial and epigenetic instability, ultimately promoting neuronal aging. Together, targeting ciliary function and its downstream regulation of TNTs and exosomes may provide a novel approach for slowing or halting disease progression across neurodegenerative diseases. Full article

Meester–Loeys syndrome (MLS) is an X-linked connective tissue disorder caused by pathogenic BGN variants. We describe a family carrying a novel missense variant. The index male, initially diagnosed with Ehlers–Danlos syndrome, had joint hypermobility, multiple visceral artery aneurysms, and recurrent musculoskeletal problems. A brother of the proband had an aortic root aneurysm. Female carriers had no or only minor manifestations. Studies of the aortic wall were consistent with a dysregulation of the TGF-β/SMAD pathway and assays with reporter vectors revealed reduced canonical Wnt and TGF-β activity in cell lines expressing mutant biglycan. However, patients’ dermal fibroblasts did not show consistent differences in the nuclear abundance of β-catenin or p-SMAD2/3 compared to cells from controls. This 3-generation family expands the genetic and phenotypic spectrum of MLS and underscores the importance of considering BGN testing in hypermobility syndromes to enable early surveillance and targeted management. Full article

Background/Objectives: Neovascular age-related macular degeneration (nAMD) poses a serious threat to the eyesight of older adults, representing a leading cause of irreversible vision loss. Anti-vascular endothelial growth factor (anti-VEGF) treatments are effective but require repeated intraocular injections and show poor responses in some patients. CGK012 is a novel derivative of decursin that inhibits the Wnt/β-catenin pathway. This study aimed to elucidate the mode of action of CGK012 and examine its therapeutic effects. Methods: We performed in vitro cellular studies in a retinal pigment epithelial (RPE) cell line (ARPE-19) and human umbilical vein endothelial cells (HUVECs). We examined the in vivo efficacy of CGK012-loaded implants in laser-induced choroidal neovascularization (CNV) rabbit models. We also determined the implants’ in vitro dissolution, intraocular release, and disposition characteristics. Results: CGK012 decreased angiogenic/proinflammatory factor expression and suppressed the epithelial–mesenchymal transition (EMT) in RPE cells by promoting intracellular β-catenin degradation. Additionally, it repressed the expression of cyclin D1 and c-myc, downstream target genes of β-catenin, and inhibited HUVEC capillary tube formation. CGK012-loaded poly (lactic-co-glycolic acid) (PLGA) intravitreal implants significantly reduced vascular leakage in a laser-induced CNV rabbit model. Notably, CGK012 released from the implant was highly permeable to retina/choroid tissue and downregulated β-catenin, angiogenic/inflammatory factors, and vimentin in the rabbit model. The CGK012 concentration reached a plateau at 28–42 days in the vitreous humor and decayed with a half-life of 14 days without systemic exposure. Conclusions: Our findings demonstrate that CGK012 implants prevent choroidal neovascularization through the Wnt/β-catenin pathway suppression and produce high concentrations of CGK012 in the posterior eye segment with prolonged release. Thus, these implants provide more therapeutic choices for nAMD treatment. Full article

Renal cell carcinoma (RCC) features a complex tumor microenvironment, where cancer-associated fibroblasts (CAFs) play key roles in tumor progression, epithelial–mesenchymal transition (EMT), immune evasion, and resistance to treatment. This article updates our understanding of CAF origins, diversity, and functions in RCC, incorporating recent single-cell RNA sequencing (scRNA-seq) data that refine CAF subtypes. The paper explores the mechanistic interactions between CAFs and EMT, focusing on CAF-derived signaling pathways like TGF-β, IL-6/STAT3, HGF/c-MET, and Wnt/β-catenin, as well as extracellular-vesicle-mediated transfer of miRNAs and lncRNAs that promote metastatic behavior in RCC. It also addresses how CAF-driven remodeling of the extracellular matrix, metabolic changes, and activation of YAP/TAZ contribute to invasion and resistance to therapies, particularly in relation to tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint blockade. The review highlights emerging therapeutic strategies targeting CAFs, such as inhibiting specific signaling pathways, disrupting CAF–tumor cell communication, and selectively depleting CAFs. In conclusion, it identifies limitations in current CAF classification systems and proposes future research avenues to improve RCC-specific CAF profiling and exploit the CAF–EMT axis for therapeutic gain. Full article

Parkinson’s disease (PD) is a neurodegenerative pathology defined by specific, distinctive signs, primarily the progressive loss of dopaminergic neurons (DAergic) in the substantia nigra pars compacta (SNpc), associated with gliosis phenomena. The mechanisms that trigger the degeneration of DAergic neurons are not yet fully elucidated, although it is recognized that the interaction between genetic and environmental factors acts as a critical modulator of neuronal vulnerability. Strong evidence points to glial reactivity as a central element in PD pathophysiology; however, it remains a controversial topic whether this activation has a protective effect or, on the contrary, whether it contributes to exacerbating DAergic neuronal loss. The use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)—a neurotoxic substance—represented a turning point in Parkinson’s research, allowing the clarification of various molecular mechanisms of the disease. The primary aim of this review is to explore the current state of knowledge regarding the role of astrocytes in the processes of DAergic neurodegeneration, neuroprotection, and neurorepair. We focused on the relationship between astrocytic origin factors and neurogenic signals that mediate MPTP-induced plasticity in DAergic neurons of the nigrostriatal system. The contribution of reactive astrocytes in promoting DAergic neurogenesis starting from Neural Stem/Progenitor Cells (NPCs) present in the adult midbrain is also analyzed. Among the mediators released by astrocytes, we have previously identified the Wnt/β-catenin signaling pathway as a fundamental element capable of positively influencing neuroplasticity and dopaminergic neuronal repair induced by the toxic MPTP. In conclusion, deciphering the intrinsic plasticity of nigrostriatal DAergic neurons and signals that facilitate communication between astrocytes and NPCs is crucial for the identification of potential therapeutic targets aimed at stimulating neuronal repair. Full article

Background: Adenomyosis and endometriosis are complex, estrogen-dependent gynecological conditions increasingly diagnosed in adolescents. While traditionally considered diseases of reproductive-age women, emerging evidence suggests a possible developmental origin in some cases, with genetic and epigenetic susceptibility playing a central role. Understanding the contribution of hereditary and molecular factors in adolescent-onset forms may offer insights into early pathogenesis, personalized risk stratification and tailored prevention strategies. Objectives: The objectives of this study were to explore the current evidence supporting a genetic contribution to the development of adenomyosis and endometriosis in adolescents and to identify specific genetic variants, molecular pathways and epigenetic mechanisms potentially involved in early-onset disease. Methods: A narrative literature review was conducted using PubMed and Scopus databases up to September 2025. Studies investigating the genetic basis of adenomyosis and endometriosis in adolescents, including familial aggregation, twin studies, GWAS and candidate gene analyses, were included. Results: Evidence from familial clustering and twin studies suggests a significant heritable component in both conditions. Genome-wide association studies have identified susceptibility loci, particularly involving WNT4, VEZT and ESR1, that may be relevant to adolescent-onset disease. Candidate gene studies further highlight the roles of estrogen signalling, inflammatory pathways, extracellular matrix remodelling and emerging epigenetic alterations, including aberrant DNA methylation and chromatin remodelling, which may influence early lesion development. However, most data are derived from adult cohorts, with limited adolescent-specific analyses. Conclusions: Genetic and epigenetic predispositions appear to contribute significantly to the pathogenesis of endometriosis and possibly adenomyosis in adolescents. Further studies targeting early-onset disease are needed to unravel developmental mechanisms and gene–environment interactions unique to this population. Full article

Cochlear implants are highly successful in restoring speech perception but variability in outcomes exists. Post-surgical fibrosis and neo-ossification are thought to play a significant role, being linked to increased impedance and loss of residual hearing and posing challenges for re-implantation. Hence, there is growing interest in pharmacological interventions to limit intracochlear fibrosis and neo-ossification. While current approaches focus on steroids, studies in other organs have identified many candidate drugs. However, selection is hindered by a limited understanding of the molecular and cellular mechanisms driving fibrosis after implantation. This review introduces potential drug candidates for cochlear implant-induced fibrosis, with many targeting core fibrotic pathways such as TGF-β/SMAD, PDGF, and Wnt/β-catenin or inhibiting pro-inflammatory signalling. By drawing on lessons from other tissues, this review identifies mechanisms and therapeutic approaches adaptable to the cochlea. Understanding fibrosis across organs will guide strategies to prevent or reverse cochlear fibrosis. Their translation requires careful evaluation of local delivery, minimal ototoxicity, and effects on the electrode–tissue interface. Full article

Endothelial-to-mesenchymal transition (EndMT) is a cellular program implicated in fibrosis, vascular remodeling, and the tumor microenvironment across multiple organs. We synthesize mechanistic pathways including TGF-β/SMAD, non-canonical (MAPK, PI3K/AKT, Rho/ROCK), Notch, and Wnt/β-catenin cascades. Their crosstalk with hypoxia, inflammatory cues, and epigenetic mechanisms can drive loss of endothelial identity and acquisition of mesenchymal characteristics. We outline disease contexts in the heart, lungs, kidneys, liver, central nervous system, and cancer, highlighting context-dependent contributory roles of EndMT. Therapeutically, we review pathway-targeted agents, epigenetic inhibitors, microRNA-based strategies, antibodies/biologics, small molecules and natural compounds, and cell- and gene-based interventions. Finally, we outline a translational roadmap that pairs patient-derived iPSC/organoid and organ-on-a-chip platforms to stratify EndMT states and prioritize targets. We also explore combination regimens that integrate multi-pathway modulation with epigenetic and immune approaches, aiming to deliver clinically meaningful anti-fibrotic benefits while better preserving physiological signaling. Full article