Search Results (1,674)

Orthodontic tooth movement has traditionally been planned according to biomechanical principles; however, growing evidence indicates that treatment outcomes are strongly influenced by individual biological responsiveness. This narrative review summarizes current knowledge on the mechanobiological and molecular mechanisms regulating periodontal tissue remodeling during orthodontic tooth movement and discusses their implications for personalized orthodontic treatment. The literature was critically analyzed with particular emphasis on mechanotransduction pathways, including Piezo1, TRPV4, integrin-mediated signaling, Hippo-YAP/TAZ, Wnt/β-catenin, and the RANK/RANKL/OPG axis, together with inflammatory mediators, extracellular matrix remodeling, periodontal phenotype, and emerging molecular biomarkers associated with periodontal susceptibility. Recent advances in cone-beam computed tomography, intraoral optical scanning, STL-CBCT fusion, and artificial intelligence were also reviewed for their potential to improve biologically informed diagnosis and treatment planning. Current evidence indicates that periodontal complications, including gingival recession, alveolar bone loss, and root resorption, arise from complex interactions between orthodontic biomechanics and patient-specific biological characteristics rather than tooth movement alone. Integration of mechanobiology, molecular profiling, advanced imaging, and artificial intelligence provides the foundation for precision orthodontics, enabling individualized risk assessment, biologically guided treatment planning, and improved long-term periodontal stability. Full article

Multiple myeloma (MM) is an incurable hematological malignancy. SOX7, located within the recurrently deleted 8p23.1 region in MM, is suggested to act as a tumor suppressor. We characterized SOX7 through genetic, epigenetic, and functional analyses in MM cell lines. SOX7 was frequently silenced due to deletion and/or promoter hypermethylation. Ectopic SOX7 expression in KMS-18 and MM.1S cell lines caused a progressive decline in SOX7-transduced cells and induced G1 cell cycle arrest and/or apoptosis. Although SOX7 re-expression did not enhance bortezomib efficacy, treatment with the pan-histone deacetylase inhibitor panobinostat induced G1 arrest, promoted apoptosis, and increased SOX7 expression in MM.1S cells. Whole-transcriptome sequencing identified G1/S progression-related Wnt/β-catenin pathway genes as major SOX7-regulated targets, while ChIP-Seq analysis revealed widespread genomic SOX7 occupancy in MM.1S. Flow cytometric analysis of permeabilized bone marrow tumor cells from newly diagnosed and relapsed MM patients demonstrated generally low SOX7 protein expression. Collectively, these results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression. The anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction. Full article

Objective: This research examined the effectiveness of liposomal N-Curcumin (N-Cur) against Cis-diamminedichloroplatinum (CDDP)-induced hepatotoxicity, specifically examining its ability to influence the Wnt/β-catenin/GSK-3 pathway and associated molecular markers. Methods: Male Wistar rats were treated for 14 days with oral N-Cur (80 mg/kg) and with a single intraperitoneal dose of CDDP (7 mg/kg) administered on day 7. Hepatic integrity was assessed through liver injury markers, histopathological examination, and biochemical analysis of oxidative stress (SOD, GSH, and MDA), inflammation (IL-10, TNF-α, CRP, and NF-κB p65), and signaling protein expression (β-catenin, Nrf2, and GSK-3). Results: CDDP administration resulted in significant hepatic damage, characterized by elevated injury markers and distorted tissue architecture. It induced severe oxidative stress (increased MDA; decreased GSH and SOD) and a robust inflammatory response. At the molecular level, CDDP suppressed the cytoprotective β-catenin and Nrf2 pathways while increasing GSK-3. Conversely, N-Cur treatment effectively reversed these pathological shifts by restoring antioxidant defenses, inhibiting pro-inflammatory mediators, and normalizing the Wnt/β-catenin/GSK-3 signaling axis. Conclusions: Liposomal N-Cur demonstrates significant potential as a hepatoprotective agent when administered concomitantly with CDDP chemotherapy. N-Cur mitigates oxidative damage and inflammation, thereby preserving hepatic function during CDDP-based chemotherapy. In addition, these favorable effects were associated with modulation of the Wnt/β-catenin/GSK-3 and Nrf2 pathways. Full article

Bone remodeling is rhythmically regulated, yet the contribution of the circadian–melatonin axis to osteoporosis remains incompletely defined, in part because mechanistic findings obtained at high experimental concentrations are frequently extrapolated to physiological signaling. This narrative review examines that inference. PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched from inception to July 2026 for English-language studies of melatonin, circadian clock genes, and bone; molecular, preclinical, epidemiological, and clinical evidence was appraised with attention to receptor dependence, exposure concentration, and study architecture. In osteoblast-lineage cells, melatonin promotes osteogenic differentiation through MT2-linked Wnt/β-catenin and MEK1/2–MEK5 signaling, post-translational stabilization of SP7, and modulation of the OPG/RANKL axis. By contrast, direct antiosteoclastic and antioxidant effects are usually reported at micromolar concentrations, four to six orders of magnitude above nocturnal plasma levels, and are increasingly attributable to receptor-independent chemistry converging on the ROS–KEAP1–NRF2 node shared with structurally unrelated antioxidant compounds. This exposure mismatch suggests that conventional oral doses engage receptor-mediated osteoblast pathways rather than reproduce high-dose antiresorptive effects; sustained exposure at or above 1 µM is not attainable by conventional oral administration, and the chronic safety of the doses that would be required has not been characterized. In humans, bone resorption has an intrinsic circadian rhythm, and night-shift work is associated with adverse skeletal outcomes, although causality remains unresolved. The five available randomized trials are small and heterogeneous; none was powered for fracture prevention, and none compared administration times for a skeletal endpoint. Melatonin therefore cannot currently be recommended for the treatment of osteoporosis. Human bone and marrow pharmacokinetics, receptor-specific in vivo dose–response experiments, and adequately powered monotherapy trials in established primary osteoporosis are the studies that would change this assessment. Full article

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

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

The intestinal epithelium is a dynamic tissue renewed by intestinal stem cells (ISCs) within the crypt niche. ISC behavior is regulated not only by intrinsic genetic programs but also by dietary composition, nutrient availability, microbial metabolites, and feeding rhythms. This narrative review synthesizes mechanisms through which diet influences ISC self-renewal, proliferation, differentiation, metabolic programming, and regenerative capacity. Dietary patterns exert context-dependent effects: caloric restriction, fasting, and structured feeding–fasting cycles may enhance epithelial regeneration through nutrient-sensing pathways, mitochondrial adaptation, and circadian regulation, whereas Western-type and high-fat diets may promote niche remodeling, inflammation, metabolic reprogramming, and tumorigenic risk. Macronutrients regulate ISC fate through carbohydrate metabolism, amino acid sensing, fatty acid oxidation, and lipid-derived signaling molecules. Micronutrients, including vitamins A, D, and B and minerals such as iron, zinc, selenium, and magnesium, contribute to epithelial differentiation, redox balance, and barrier integrity. Phytochemicals may modulate ISC function through Wnt/β-catenin, Nrf2, SIRT1, and epigenetic pathways or by stabilizing the epithelial microenvironment. The gut microbiota mediates diet–ISC interactions via short-chain fatty acids, bile acids, indole derivatives, and other metabolites. However, human evidence remains limited, and studies integrating human organoids, single-cell analyses, metabolomics, and chrononutrition are needed to inform personalized nutritional strategies for intestinal health. Full article

Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence. Full article

Polyphosphate (PolyP) is an inorganic polymer composed of orthophosphate units linked by high-energy phosphate anhydride bonds, widely found in various organisms from bacteria to mammals. In recent years, PolyP has attracted widespread attention in the field of bone tissue engineering due to its unique biological characteristics, possessing both osteoinductive activity and metabolic energy supply functions. This article systematically reviews the molecular structure, physicochemical properties, and multiple mechanisms by which PolyP promotes osteogenic differentiation, as well as biomaterial design strategies based on PolyP. PolyP can synergistically promote osteogenic differentiation through multiple mechanisms, including by acting as a phosphate donor, providing metabolic energy, regulating signaling pathways such as Wnt/β-catenin, and modulating the osteoprotegerin/receptor activator of nuclear factor κB ligand (OPG/RANKL) balance. In terms of material design, PolyP can form nano/microparticles with metal ions such as Ca²⁺, Sr²⁺, and Mg²⁺ and can also be compounded with polymers to construct various forms such as hydrogels, bone cement, and three-dimensional (3D)-printed scaffolds. Preclinical studies have shown that PolyP-incorporated materials exhibit excellent osteogenic performance and biocompatibility in bone defect repair, and preliminary clinical studies have also confirmed its feasibility. This article aims to provide a comprehensive overview of the current applications of PolyP-incorporated materials and delineate future directions, challenges, and necessary pathways for their clinical translation. Full article

Background/Objectives: The emergence of radioresistance is a major challenge in cancer treatment. Herein, we evaluated the radiosensitizing effects and associated molecular mechanisms of a small molecule, berberine, in HNSCC. Methods: HNSCC cells were treated with berberine, ionizing radiation (IR), and their combination. Radiosensitivity was assessed using methods for clonogenic survival, proliferation, cell death, apoptosis, cell cycle distribution, DNA damage, and associated mechanisms. Spheroid models were employed to examine tumor growth and stemness-related markers. Therapeutic efficacy was further evaluated using the syngeneic MOC2 tumor syngraft mouse model. Results: The combination of berberine and IR significantly decreased the colony-forming ability, cell proliferation, and survival in UM-SCC-22B and MOC2 cells. Correspondingly, a decrease in the pro-survival signaling, EGFR, ERK1/2, mTOR, and STAT-3 was noted. The combination treatment increased sub-G1 cell population and apoptotic cell death with enhanced DNA damage, which was also associated with downregulation of DNA repair proteins. Spheroids showed disintegration and altered morphology in the combination treatment. This combination also inhibited Wnt/β-catenin signaling and reduced the expression of genes associated with stemness-related pluripotency. Berberine further enhanced DNA damage and reduced stemness in EGFR-knockdown cells. The berberine-IR combination not only inhibited the growth of syngeneic MOC2 tumors but also mitigated the toxicity associated with IR. The in vitro findings of reduced expression of stemness and DNA damage repair genes were also observed in tumors. Conclusions: Our findings indicated that berberine enhances the radiation response of HNSCC through perturbation of pro-survival signaling, DDR signaling and reduction of stemness-associated features, thereby enhancing the therapeutic efficacy. Full article

Background: Tankyrase 1 (TNKS1) is a poly(ADP-ribose) polymerase involved in Wnt/β-catenin signaling, telomere maintenance, and genomic stability, making it an attractive therapeutic target in oncology. This study aimed to develop and apply an integrated computational workflow to identify novel TNKS1 inhibitor candidates. Methods: A curated dataset of experimentally validated TNKS1 inhibitors and property-matched DUD-E decoys was used to develop a consensus supervised machine learning (ML) model prioritization framework for ligand-based virtual screening, integrating Morgan fingerprints with three complementary classifiers. The model screened more than 700,000 compounds, and prioritized hits were evaluated by structure-based virtual screening (SBVS), Prime MM-GBSA binding free-energy refinement, and 500 ns molecular dynamics simulations (MDs). The top candidates were subsequently tested in an in vitro TNKS1 enzymatic inhibition assay. Results: The consensus ML framework prioritized 670 compounds, yielding five candidates for experimental testing. Compound 3 displayed the most favorable computational profile and was experimentally confirmed as a TNKS1 inhibitor candidate, exhibiting approximately 80% TNKS1 inhibition at 0.1 μM, whereas the remaining candidates showed only limited activity. Conclusions: The proposed workflow efficiently reduced a large chemical space to a focused set of TNKS1 inhibitor candidates while substantially reducing the experimental screening burden. Compound 3 represents a promising starting point for future structure–activity relationship studies and lead optimization in the context of TNKS1 inhibition. Moreover, this work highlights the value of integrating consensus ML, SBVS, and experimental validation to accelerate early-stage hit discovery for TNKS1 and other therapeutic targets. Full article

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare malignancy in which overexpression of steroidogenic factor-1 (SF-1/NR5A1) and aberrant activation of canonical Wnt/β-catenin signaling are important oncogenic events. However, the extent to which these regulatory axes converge or interact at the transcriptional level remains unclear. We investigated their relationship using bulk transcriptomic and regulatory-network approaches. Methods: Regulatory network inference using RTN/ARACNe was applied to the TCGA-ACC cohort. NR5A1 and β-catenin-associated TCF/LEF regulon activities were evaluated in perturbation datasets and tested for associations with CpG island methylator phenotype (CIMP), overall survival, and gene-level interaction effects. Candidate modulators of NR5A1 activity were assessed using the MINDy algorithm. The effects of cBAF inhibition on NR5A1 regulon activity were also evaluated in H295R and CU-ACC1 cells. Results: NR5A1 knockdown repressed steroidogenic pathways, whereas β-catenin knockdown predominantly suppressed Wnt/β-catenin signaling. In TCGA-ACC, NR5A1 regulon activity was associated with CIMP-high status and overall survival. In contrast, β-catenin-related regulons were not significantly associated with CIMP-high status after adjustment for NR5A1 activity, and no significant multiplicative interaction effects were identified. Fewer than 3% of protein-coding genes showed improved fit in models including NR5A1 × TCF/LEF interaction terms, without enrichment for steroidogenic or Wnt/β-catenin-related pathways. CTNNB1 was identified as a statistically significant but low-ranking positive modulator of NR5A1 activity, whereas CTNNBIP1 was a top-decile negative modulator. cBAF inhibition was associated with NR5A1 regulon repression in both cell models. Conclusions: These findings indicate limited detectable global transcriptional convergence between NR5A1 and canonical β-catenin-related regulons in the evaluated bulk transcriptomic frameworks. Potential relationships between these pathways may depend on more localized, chromatin-dependent, protein-level, or context-specific regulatory mechanisms. NR5A1 regulon activity showed more consistent associations with CIMP-high status and clinical outcome than the β-catenin/TCF-LEF regulons in the evaluated TCGA-ACC models. The modulation patterns associated with CTNNB1 and CTNNBIP1, together with the repression of NR5A1 regulon activity following cBAF inhibition, raise the possibility that NR5A1 acts as a context-dependent regulatory node connecting oncogenic signaling and chromatin-remodeling mechanisms in ACC. These findings support further investigation into the role of chromatin-remodeling complexes in sustaining NR5A1-driven transcriptional programs in ACC. Full article

Melatonin, a methoxyindole synthesized by the pineal gland, is secreted in response to photoperiodic cues relayed from the retina through an endogenous circadian oscillator within the suprachiasmatic nucleus. Consequently, melatonin secretion regulates the circadian rhythm. Melatonin has been reported to have antioxidant, photoprotective, anti-inflammatory, anticancer, and wound-healing properties. It has also been reported to promote hair growth, although the underlying mechanisms remain unclear. In this study, we explored the potential molecular mechanisms of melatonin-induced hair growth by using an in vivo C57BL/6 mouse model. We observed morphological changes in the dorsal area and changes in the hair cycle and anagen induction were observed through hematoxylin–eosin staining. The molecular mechanisms were explored using Western blotting and immunofluorescence assay. Our findings indicate that topical melatonin promotes anagen entry and hair regrowth in C57BL/6 mice, accompanied by the modulation of Wnt/β-catenin-related signaling proteins. The decrease in grayscale value, increase in hair length and skin thickness and histological change in hair follicles in the melatonin-treated group indicated hair regrowth in the dorsal skin of mice. Moreover, the expression of the Wnt/β-catenin pathway was remarkably regulated. These findings further our understanding of the molecular mechanisms underlying topical melatonin-induced hair growth. Full article

Oxidative stress contributes to hair follicle aging, melanocyte dysfunction, and androgen-related hair disorders, yet chemically characterized botanical interventions with multi-target activities remain incompletely defined. This study evaluated the antioxidant, follicle-supporting, and antiandrogenic potential of Eucommia ulmoides bark extract (EUE) using integrated in vitro and in vivo approaches and characterized EUE by HPLC-DAD using geniposidic acid and chlorogenic acid as representative marker compounds. Chlorogenic acid and geniposidic acid were present at 3.21 ± 0.01 and 1.88 ± 0.15 mg/g extract, respectively. In replicate-well assays using H₂O₂-challenged B16 melanoma cells, EUE increased superoxide dismutase activity and reduced malondialdehyde accumulation. Technical-triplicate RT-qPCR measurements and a single Western blot experiment showed descriptive changes in Nrf2 and HO-1 markers; these observations are exploratory and require independent biological replication. In HDPCs, replicate-well viability assays and technical-triplicate RT-qPCR measurements indicated concentration-associated viability changes and descriptive changes in VEGF, Wnt5a, and β-catenin transcripts. EUE also inhibited 5α-reductase activity in a cell-free assay, although the non-monotonic response and the much higher mass concentrations used relative to finasteride preclude potency equivalence. In male C57BL/6 mice, topical EUE attenuated H₂O₂-induced suppression of hair follicle elongation and improved follicular morphology. Overall, EUE is a chemically characterized botanical extract with preliminary biological activities relevant to oxidative stress- and androgen-associated hair disorders; independent replication, active-compound identification, marker-specific permeation, and protein-level validation of the measured markers remain necessary. Full article

Vascular calcification (VC) is a major complication of chronic kidney disease (CKD) that is strongly associated with cardiovascular mortality. While indoxyl sulfate (IS), a protein-bound uremic toxin, has been implicated in the progression of VC, the underlying molecular mechanisms remain unclear. We investigated the procalcific effects of IS using a two-step nephrectomy-induced CKD mouse model and cultured vascular smooth muscle cells. In vivo, progressive renal impairment was associated with elevated circulating IS levels and enhanced VC. In vitro, IS dose- and time-dependently induced calcium deposition, increased reactive oxygen species (ROS) production, and upregulated osteogenic markers, including runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), and osteocalcin (OCN), whereas N-acetyl-L-cysteine (NAC) partially attenuated IS-induced ROS accumulation and cell injury. Mechanistically, IS exposure activated extracellular signal-regulated kinase (ERK) and Wnt/β-catenin signaling while suppressing nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant responses, as reflected by reductions in the phosphorylated Nrf2 (pNrf2) to total Nrf2 and heme oxygenase-1 (HO-1) expression. Pharmacological inhibition of ERK and Wnt/β-catenin signaling attenuated IS-induced osteogenic responses. These findings indicate that IS promotes VC in association with increased oxidative stress, activation of ERK and Wnt/β-catenin signaling, and impaired Nrf2-related antioxidant defense. These integrated findings provide mechanistic insight into IS-associated VC and highlight oxidative stress-related signaling networks as potential therapeutic targets in CKD. Full article