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The retinal pigment epithelium (RPE) plays a pivotal role in retinal homeostasis and energy metabolism. A recent study demonstrates that RPE cells release insulin in response to photoreceptor outer segment (POS) phagocytosis and starvation conditions. However, the downstream signalling pathway of this local insulin production has not yet been identified. Therefore, using the ARPE-19 cell line as an in vitro model of human RPE, we have investigated insulin signalling in basal conditions and after rod OS phagocytosis. Our data show that ARPE-19 cells express key pancreatic β-cell markers, including the transcription factor Pancreatic and Duodenal Homeobox-1 (PDX-1), which translocates to the nucleus in response to phagocytosis, and prohormone convertase 1/3 (PC1/3). In addition, ARPE-19 cells synthesize and secrete insulin already in basal conditions, increasing their release after phagocytosis. The RPE-secreted insulin acts in an autocrine manner, activating the canonical insulin signalling pathway and leading to increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and AKT. An upregulation of the insulin-responsive glucose transporter GLUT4 and increased glucose uptake was also observed, fueling the ARPE-19 cells' oxidative energy metabolism, incrementing the oxidative phosphorylation activity, probably to sustain the high energy demand associated with phagocytosis. At the same time, a decrease in lactate release has been observed. These features may have important implications for understanding retinal energy metabolism and developing novel therapeutic strategies for retinal neurodegenerative diseases.
Stem cell-based bone tissue engineering is often limited by insufficient osteogenic differentiation and inadequate vascularisation, largely attributable to the absence of a biomimetic stem cell niche. This study aimed to develop a human gingiva-derived decellularised extracellular matrix hydrogel (G-dECM) as a supportive microenvironment for three-dimensional (3D) coculture spheroids of STRO-1⁺ gingival mesenchymal stem cells (sGMSC) and human umbilical vein endothelial cells (HUVEC), thereby promoting the expression of osteogenic and angiogenic markers. Human gingival tissue was processed through decellularisation, enzymatic digestion, and sol-gel transformation to prepare G-dECM hydrogel. Composite 3D sGMSC/HUVEC spheroids (GHS) were generated and encapsulated within G-dECM. Morphological assessment, viability evaluation, and osteogenic differentiation analyses were conducted. Transcriptomic profiling was performed to identify G-dECM-associated regulatory signalling pathways. G-dECM exhibited a porous, collagen-rich structure enriched with bioactive ECM proteins. Encapsulation of GHS within G-dECM enhanced cellular viability, promoted the expression of osteogenic and angiogenic markers, and improved spheroid structural integrity compared with matrix-free controls. Transcriptomic analysis revealed activation of TGF-β/SMAD and BMP signalling pathways associated with osteogenic differentiation. G-dECM provides a biomimetic stem cell niche that supports the osteogenic and angiogenic phenotypes of 3D sGMSC/HUVEC spheroids, establishing an integrated regenerative graft system combining seed cells, scaffold, and endogenous signalling cues. This G-dECM-based composite graft strategy offers a promising translational approach for the regeneration of alveolar bone defects associated with periodontal disease, trauma, or tooth extraction.
Ultrasound mediated microbubble cavitation holds great potential for non-invasive and targeted drug delivery. However, the interplay between acoustic parameters, bubble dynamics, and resulting cellular responses remains unclear, hindering the safety improvement and optimization of the technique. This study examined the effects of ultrasound pulse sequences on microbubble dynamics and bioeffects in endothelial monolayer using an acoustically coupled vessel-mimicking microchannels, where focused ultrasound exposure and concurrent recording of Ca2+ signalling and membrane perforation were performed at flow conditions. A reduction of the total treatment time from 60 to 10 s avoided cell detachment. Microbubbles demonstrated brief oscillation and displacement under each of the 10 consecutive bursts of 40  µs short pulses with 1 ms interval while more intense bubble clustering, coalescence and displacement were observed under one continuous long pulse that lasted for around 9 ms. 10 s long pulse generated higher percentage and larger extent of cell membrane poration whereas short pulse induced wider spreading and larger Ca2+ signalling across the cell population. Reactive oxygen species, extracellular Ca2+ influx through mechanosensitive channels and internal Ca2+ release were found critical in mediating Ca2+ responses in short pulse condition. Further transwell experiments revealed that both pulse modes enhanced transport of 10  kDa FITC-dextran while a longer treatment of 60 s improved delivery efficiency for larger FITC-dextran of 40 kDa. These findings highlight the importance of pulse modes and total treatment time in tailoring Ca2+ signalling mediated paracellular transport and sonoporation mediated transcellular transport, offering insights for optimizing ultrasound parameters for therapeutic drug delivery.
Lipopolysaccharide (LPS) triggers signal transduction in dental pulp cells (DPCs), leading to various biological events. The present study described the biological response of DPCs to LPS, aiming to provide a deeper understanding of its mechanisms. A literature search was performed in PubMed, Web of Science and Google Scholar using the keywords 'lipopolysaccharide', 'dental pulp cells' and 'dental pulp stem cells'. Original studies and review articles published in English that investigated cellular or molecular responses of pulp-derived cells to LPS stimulation were included. A narrative review was then conducted to summarise and discuss the effects of LPS on these cells. Across the selected studies, LPS exposure consistently activates intracellular signalling cascades in DPCs, leading to a series of downstream events, including inflammatory cytokine production, oxidative stress generation, mitochondrial impairment, premature cellular senescence and alterations in odonto/osteogenic differentiation. These interconnected molecular changes underpin the progression of pulpal inflammation and influence the tissue's capacity for repair or regeneration. This narrative review described the biological response of DPCs to LPS, providing deeper insight into its mechanisms. Understanding LPS-mediated signalling enables clinicians to tailor regenerative therapeutic approaches and vital pulp therapies by modulating inflammation and optimising biological events to support dental pulp tissue healing and dentine regeneration.
The ribosome has emerged as a signalling hub that can sense metabolic perturbations and coordinate responses that either restore homeostasis or initiate cell death. The range of insults that signal via the ribosome and the mechanisms governing such cell fate decisions remain uncharacterized. Here we identify the atypical E3 ligase HOIL-1 as an unexpected node in the ribosome signalling network that resolves cellular stress. We find that truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice and broadly sensitize cells to nutrient and translational stress. These diverse signals converge on the MAP3K ZAKα, a sentinel of ribotoxic stress. Mechanistically, HOIL-1 promotes ribosome ubiquitination and facilitates cytoprotective ribosome-associated quality control. HOIL-1 loss of function causes glucose starvation to become ribotoxic, leading to ZAKα-dependent ATF4 activation and disulfidptosis driven by the cystine-glutamate antiporter xCT. These data reveal a molecular circuit controlling cell fate during nutrient stress and establish the ribosome as a signalosome that responds to cellular glucose levels.
Connexin 43 (Cx43) exhibits remarkable functional diversity that is precisely dictated by its dynamic subcellular localization. Beyond its canonical role at the plasma membrane, where it assembles into gap junctions (GJs) and hemichannels (HCs) to mediate intercellular communication, Cx43 translocates to the nucleus and mitochondria, where it exerts non-channel functions including transcriptional regulation and metabolic adaptation. At the plasma membrane, dysregulation of Cx43 trafficking, anchoring, or turnover leads to excessive HC opening and impaired GJ communication, contributing to cardiovascular arrhythmias, ischemia-reperfusion injury, neuroinflammation, osteoporosis, and retinopathy. In the nucleus, Cx43 or its C-terminal fragment enters through importin-dependent pathways, functioning as a non-canonical transcriptional regulator; its mislocalization is implicated in cancer (context-dependent suppression or promotion), hepatic gluconeogenesis in diabetes, and tissue fibrosis. Within mitochondria, Cx43 is imported via Hsp90/TOM complex- or GJA1-20 k-dependent pathways, where it regulates K+ transport, respiratory chain activity, and redox balance; this mitochondrial pool exerts cardioprotection under preconditioning but exacerbates diabetic cardiomyopathy and neurological injury under pathological stress. This review synthesizes current knowledge on the trafficking mechanisms, pathological outcomes, and therapeutic targeting of Cx43 in these three subcellular compartments. We further discuss peptide-based inhibitors (e.g., Gap19, αCT1), small molecules (e.g., tonabersat, danegaptide), and natural product-derived modulators, highlighting challenges in specificity, bioavailability, and clinical translation. By linking compartment-specific functions to distinct disease entities, this review establishes subcellular localization as a central determinant of Cx43 biology and a promising axis for precision medicine.
The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood-retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues.
Silicosis, a fibrotic lung disorder triggered by inhalation of respirable crystalline silica (silicon dioxide, SiO₂) dust exposure, involves chronic inflammation, oxidative stress, and immune dysregulation as key pathogenic mechanisms. Evidence has identified Notch1 signalling as a determinant in disease progression through its regulatory influence on inflammatory activity, fibrotic remodeling, and immune cell function. The present study integrated animal models, cellular assays, and coculture systems to delineate the regulatory impact of Notch1 signalling on macrophage polarization and fibrosis. In vivo, silica exposure provoked fibrotic lesions, markedly enhanced pulmonary M1/M2 macrophage marker expression (iNOS, IL-1β, Arg1, and CD206), and activated Notch1 signalling. In vitro, silica displayed dual effects dependent on concentration and duration. At low doses (<50 μg/mL), M2 polarization predominated, whereas higher doses (≥200 μg/mL) primarily induced M1 polarization accompanied by reduced viability. Regarding temporal dynamics, short exposure (6h) triggered Notch1 activation and acute M1 polarization, while longer exposure (>6 h) shifted the balance toward M2 dominance. Pharmacological modulation with DAPT (Notch inhibitor) and valproic acid (VPA, Notch activator) demonstrated a direct correlation between Notch1 activity and M1 polarization intensity. Coculture assays further indicated that Notch1 activation synergistically reduced fibrotic marker expression (Vimentin, α-SMA) in epithelial cells, pointing to suppression of fibrosis through immune-stromal crosstalk. Collectively, the findings define a dynamic Notch1-macrophage polarization axis in silicotic fibrosis and provide a conceptual framework for stage-specific therapeutic strategies directed at this pathway.
Osteoporosis is a prevalent skeletal disorder characterised by progressive reduction in bone mass, microarchitectural deterioration, and increased fracture susceptibility. In India, approximately one-third of the elderly population is affected by bone-related disorders, and the global burden of osteoporosis continues to rise. Despite its significant impact on morbidity, mortality, and quality of life, current diagnostic approaches and therapeutic strategies remain suboptimal due to limitations such as prolonged treatment duration, poor patient adherence, low oral bioavailability of first-line therapies, and potential cardiovascular risks associated with some anti-resorptive agents. Given these challenges, there is an urgent need to develop safer and more effective preventive and therapeutic interventions. However, rational drug design and targeted therapies require a comprehensive understanding of osteoporosis pathophysiology. In this review, we provide an integrated overview of normal bone remodelling, key cellular players, and the mechanisms underlying impaired bone homeostasis in osteoporosis. We discuss the roles of osteoblasts, osteoclasts, and their progenitor cells, along with critical regulatory factors governing their differentiation and function. Later, we have discussed the core mechanisms and pathways involved in the pathophysiology of osteoporosis, including the RANKL-OPG axis, Wnt/β-catenin signalling, Parathyroid hormone (PTH)/PTH1R (cAMP/PKA vs. sustained Ca2+/PKC) signalling, TGF-β/BMP-SMAD signalling, etc. Furthermore, we summarise the major risk factors, including ageing, sex hormones, nutritional deficiencies, lifestyle factors, and comorbidities and delineate their mechanistic links to bone loss. This comprehensive synthesis aims to enhance understanding of osteoporosis pathogenesis and to facilitate the identification of novel molecular targets for improved therapeutic strategies.
Liver diseases, including fatty liver, hepatitis, and cirrhosis, remain major global health challenges due to their disruption of metabolic homeostasis and detoxification processes. Redox imbalance plays a central role in liver disease progression by promoting inflammation, hepatic stellate cell activation, mitochondrial dysfunction, and fibrogenesis. Although flavonoids have historically been considered direct reactive oxygen species (ROS) scavengers, emerging evidence indicates that their biological effect at physiological concentrations are primarily mediated through modulation of intracellular redox signalling rather than simple radical neutralisation. This review highlights flavonoids as redox-modulating agents capable of restoring hepatic redox homeostasis through coordinated regulation of molecular pathways. Mechanistically, flavonoids activate the Nrf2-Keap1 axis to enhance endogenous antioxidant defences, including heme oxygenase-1 and glutathione biosynthesis enzyme, while suppressing NF-κB-mediated pro-inflammatory signalling and modulating MAPK and PI3K/Akt pathways. They also regulate mitochondrial redox balance, supporting mitophagy, metabolic adaptation, and cellular resilience to oxidative stress. In addition, flavonoid biotransformation by the gut microbiome improves intestinal barrier integrity, reduces endotoxin-driven hepatic inflammation, and contributes to gut-liver crosstalk. Collectively, these mechanisms position dietary flavonoids as multi-target redox modulators with promising therapeutic potential in chronic liver disease, although further studies are needed to improve their bioavailability and clinical translation.
Tongue squamous cell carcinoma (TSCC) is a highly aggressive malignancy where extracellular matrix (ECM) stiffening drives epithelial-mesenchymal transition (EMT). However, the specific mechanotransduction pathways and the distinction between primary and metastatic cell responses remain insufficiently defined. This study investigated how substrate stiffness regulates TSCC progression via a dual-regulatory mechanism: direct cell-intrinsic mechanotransduction and indirect stromal paracrine signalling. Two human TSCC cell lines with distinct origins, HSC-4 (metastatic) and HSC-7 (primary), were cultured on tunable collagen-coated polydimethylsiloxane (PDMS) substrates of varying stiffness (soft and stiff). Cell morphology, migration, proliferation, EMT marker expression, integrin and YAP expressions were assessed using wound healing assays, qRT-PCR and immunofluorescence staining. The involvement of actin cytoskeleton was examined using cytochalasin D. Additionally, the paracrine effects were evaluated by culturing TSCC cells with conditioned media from gingival fibroblasts (HGF-CM) cultured on different substrate stiffness. Stiff substrates induced elongated, mesenchymal-like morphology and significantly enhanced migration in TSCC cells. Increased stiffness also upregulated EMT-associated markers (CDH2, VIM, MMP2), while induced YAP nuclear translocation and increased mechanosensitive integrin expression. Disruption of the actin cytoskeleton with cytochalasin D suppressed this stiffness-induced EMT marker expressions, indicating that cytoskeletal tension mediates mechanotransduction. Furthermore, HGF-CM derived from stiff substrates significantly upregulated EMT-related expression in HSC cells. Matrix stiffness drives TSCC progression through a dual mechanism: direct actin-mediated and YAP-associated mechanotransduction and indirect stiffness-modulated fibroblast signalling. These findings highlight that mechanical cues in the tumour microenvironment differentially regulate primary and metastatic phenotypes in TSCC. Mechanical properties of the tumour microenvironment drive TSCC progression, suggesting that ECM stiffness is likely to be associated with altered TSCC phenotypes, providing a basis for future mechanobiology-focused studies on TSCC progression and management.
Human amniotic membrane mesenchymal stem cells (hAMSCs) hold strong cardioprotective potential, yet their mechanisms of action remain largely elusive. C57BL/6 mice were subjected to cardiac ischemia/reperfusion (I/R) and received intravenous (IV) 2 × 105 hAMSCs at 2, 7 or 14 days post-reperfusion. Cardiac function and MIAT/miR-150/HOXA4 signalling were assessed. Mice treated 2 days post-I/R markedly improved LVEF and reduced myocardial necrosis and fibrosis by Day 21. Minimal hAMSC engraftment, evidenced by SSEA-4 immunostaining, suggests paracrine rather than direct cellular effects. Guided by GWAS implicating miRNAs in myocardial infarction, we identified miR-150 as a key effector, finding that hAMSC upregulated cardiac miR-150 and suppressed HOXA4, a profibrotic target in ischemic myocardium. In parallel, hAMSC treatment reduced cardiac MIAT, a lncRNA that sequesters miR-150, uncovering a mechanism of cardioprotection via MIAT downregulation post-reperfusion. Notably, CRISPR-Cas9 miR-150-silenced hAMSC exhibited severely impaired cardioprotective effects compared to wild-type cells, confirming the functional role of miR-150. miR-150 was identified as a key extracellular vesicle (EV) cargo released by hAMSC under hypoxic conditions, both in vitro and in hAMSC-injected I/R mice. Strickingly, administration of miR-150-enriched EVs to mice recapitulated the therapeutic benefits of hAMSC, underscoring miR-150-5p as central mediator of hAMSC-iduced cardioprotection. hAMSCs promote cardioprotection following I/R via the MIAT/miR-150-5p/HOXA4 axis, in which miR-150-5p plays a central role. These findings provide loss-of-function evidence about the therapeutic potential of hAMSC-derived EVs as a novel cell-free exosome-based strategy for the treatment of acute myocardial infarction.
Meningioma is the most common primary brain tumour. Invasion into the brain is a diagnostic feature of grade II meningiomas and is associated with recurrence and poor prognosis. Mebendazole is a microtubule inhibitor typically prescribed as an anthelmintic. However, it has the potential to be repurposed for cancer treatment. Here, we aimed to assess the ability of mebendazole to inhibit meningioma cell invasion. Primary patient-derived meningioma cell lines were cultured as 3D spheroids and embedded in an extracellular matrix-like matrix as an in vitro model of invasion. Mebendazole-treated and untreated control spheroids were analysed by mass spectrometry-based proteomics. Untreated control spheroids were capable of invasion (9/10 grade I, 10/12 grade II). When treated with mebendazole, invasion was prevented in 89% of samples (8/9 grade I, 9/10 grade II). Mass spectrometry-based proteomics revealed differences between the two grades and between male and female samples within each grade. Overall, mebendazole reduced meningioma cell invasion via Rho GTPase signalling and altered cytoskeletal dynamics in both male and female patient-derived spheroids. Clearly, more research is needed; however, due to its high tolerability, known safety profile, low cost, and ability to attenuate meningioma cell invasiveness, mebendazole has the potential to be a good candidate for being repurposed for the treatment of meningioma.
Colorectal cancer (CRC) remains one of the most prevalent malignancies worldwide and is the second largest contributor to both incidence and mortality, underscoring the urgent need for effective prevention strategies. This comprehensive review provides the most up-to-date evidence on the protective role of plant-based dietary patterns against CRC carcinogenesis, with particular emphasis on underlying cellular and molecular level mechanisms. Accumulating research demonstrates that plant-based foods, rich in dietary fibre, polyphenols, and multiple other bioactive compounds, promote gut microbial eubiosis, support immune regulation, and modulate adipose tissue homeostasis. These effects are accompanied by intestinal barrier integrity, enhanced production of short-chain fatty acids, and the induction of apoptosis in malignant cells. Moreover, plant-derived nutrients reduce the abundance of pro-inflammatory microbial taxa, decrease oxidative, nitrosative and carbonyl stress, and downregulate pro-inflammatory cytokines and signalling pathways, implicated in tumourigenesis. As a result, plant-based dietary patterns have high potential to reduce CRC risk through modulating the intricate interplay between epigenetics, inflammation, immune dysregulation, metabolic and hormonal disruptions, and gut microbiota, suggesting a highly promising, cost-effective and equitable strategy for CRC prevention.
Preeclampsia is a severe gestational complication whose molecular pathogenesis remains poorly understood despite extensive research. It is now recognized that both maternal and fetal cells contribute to disease progression. Notably, single-cell RNA sequencing of cord blood cells from preeclamptic pregnancies has not been previously investigated, and this became the focus of our study. In this work, we performed flow cytometry, single-cell RNA sequencing and bioinformatics analysis of cord blood mononuclear cells from preeclampsia and control groups. Bulk RNA-sequencing data of preeclamptic cord blood from open source was also analysed. We observed a significant decrease in the expression of the CD3, CD8 and CD4 markers in cord blood mononuclear cells in the preeclampsia group. Single-cell RNA sequencing revealed activation of iron- and heme-associated signalling pathways in various cell types (nonclassical monocytes, naive СD4+ and CD8+ T cells, T-helpers 2, NK cells and naive СD4+ regulatory T cells) in cord blood during preeclampsia. Analysis of open-source bulk RNA-sequencing data confirmed our findings of activation of heme-related signalling pathways in preeclamptic cord blood samples. These results may suggest the activation of compensatory mechanisms, potentially mediated by the proangiogenic heme degradation products carbon monoxide and biliverdin. Additionally, free heme may act as a proinflammatory damage-associated molecular pattern in preeclampsia. Further studies are needed to elucidate the direct relationship between these mechanisms and placental heme metabolism.
To regulate immune and inflammatory responses, suppressor of cytokine signalling (SOCS) proteins bind to multiple signalling components downstream of cytokine receptors, such as Janus kinase (JAK) and signal transducers and activators of transcription (STAT). Dysfunctional SOCS proteins in immune and tissue-resident cells may contribute to chronic inflammation. Abnormal expression of SOCS proteins, including SOCS1, SOCS2, SOCS3, SOCS5, SOCS6, and SOCS7, has been reported in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), playing a vital role in disease pathogenesis. The expression of SOCS1 and SOCS3 varies across different cell types and stages of the disease. Genetic polymorphisms, epigenetic modifications, microRNAs, cytokines, hormones, therapeutic agents, and gender factors can influence SOCS1 and SOCS3 expression in MS patients and EAE mice. The functional impact of SOCS1 and SOCS3 is cell-type specific, with distinct roles in T cell subsets, microglia/macrophages, dendritic cells, astrocytes, and oligodendrocytes. In particular, SOCS1 and SOCS3 affect T cell subset differentiation, Th17/Treg cell balance, microglial/macrophage polarization, dendritic cell functions, as well as oligodendrocyte survival and activity. Therapeutic approaches targeting SOCS molecules, including SOCS1 mimetic peptides, have demonstrated promise in EAE models. This review provides a comprehensive explanation regarding the expression patterns of SOCS molecules in MS patients and EAE model, factors affecting their expression and their mechanistic role in disease immunopathogenesis, as well as highlights their potential as a therapeutic target for MS.
Repairing maxillofacial bone defects remains a major clinical challenge due to inadequate vascularisation and poor integration with host tissue. While bioactive scaffolds have shown promise in supporting osteogenesis and angiogenesis, achieving robust and synchronised dual regenerative outcomes is still elusive. This study presents a multifunctional, cell-free magnetic hydrogel platform designed to biomimetically coordinate osteogenic and angiogenic processes for effective maxillofacial bone regeneration. The composite poly(vinyl alcohol)-vaterite (PVA-Vat) hydrogel scaffold incorporates tuneable magnetic nanoparticles (MNPs) composed of single-domain superparamagnetic iron oxide (Fe3O4). By harnessing magneto-mechanical cues to orchestrate bilateral communication between human bone mesenchymal stem cells and endothelial cells, this platform provides a deeper mechanistic understanding of coupled tissue regeneration and delivers superior dual-regenerative performance for maxillofacial bone repair. Under magnetic stimulation, a coculture system demonstrated strong osteogenesis-angiogenesis coupling mediated by reciprocal VEGFA-BMP2 signalling. This reciprocal crosstalk was evidenced by a synergistic amplification of VEGFA and BMP2 expression in coculture compared to monocultures, where MNP-stimulated osteoprogenitors secreted VEGFA to drive endothelial capillary-like network formation, while endothelial cells reciprocally enhanced endogenous BMP2 levels to accelerate osteoblastic mineralisation. These findings establish MNP-integrated hydrogels as a cell-free, multifunctional platform capable of synchronising dual regenerative pathways, offering a biomimetic strategy to overcome vascularisation and integration barriers in maxillofacial bone repair.
Ubiquitination, a central post-translational mechanism, shapes the amplitude and duration of cellular signalling. Josephin domain-containing 2 (JOSD2), a Machado-Joseph disease (MJD) family deubiquitinase, eliminates ubiquitin moieties from ubiquitin-conjugated substrates and tunes proteostasis and signalling outputs. Emerging evidence links aberrant JOSD2 activity to diverse pathological states. This review, aims to summarize the current data regarding of JOSD2 as a regulatory node in ubiquitin-dependent signalling and discuss the role of its dysregulation in malignancies through interconnected mechanisms, including metabolic rewiring, rewiring of oncogenic signalling circuits, and altered therapeutic responses that promote resistance. Furthermore, the context-dependent roles of JOSD2 beyond cancer emphasized, with reported pathogenic or protective functions in cardiovascular disorders and inflammatory bowel disease. The literature highlights JOSD2 as a signalling-relevant deubiquitinase with pleiotropic, context-dependent functions. This review discusses key knowledge gaps-such as incomplete substrate mapping and determinants of tissue specificity-and outlines translational opportunities and challenges for exploiting JOSD2 as a biomarker and therapeutic target.