Extracellular Matrix Deposition Research Articles

Lysosome-Targeting Nanochimeras Attenuating Liver Fibrosis by Interconnected Transforming Growth Factor-β Reduction and Activin Receptor-Like Kinase 5 Degradation.

Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is predominantly driven by activated hepatic stellate cells (HSCs) through the TGF-β-Smad2/3 signaling pathway. A critical barrier to effective treatment has been the compensatory upregulation of the receptors, which often limits the efficacy of targeted TGF-β inhibition strategies. Our current study introduces a lysosomal targeting degradation chimera (MAP) composed of an antioxidative polydopamine (PDA) nanoparticle conjugated to the ligands specifically targeting ALK5, a TGF-β receptor I, and cation-independent mannose 6-phosphate receptor (CI-M6PR). Notably, CI-M6PR is highly upregulated on the surface of the activated HSCs. These MAPs preferentially accumulated in the fibrotic liver tissues, reduced TGF-β production by scavenging reactive oxygen species, and simultaneously recognized the activated HSCs to facilitate targeted lysosomal degradation of ALK5. The interconnected dual-enhanced mechanisms effectively inhibited the TGF-β-Smad2/3 signaling pathway in HSCs, thus diminishing ECM secretion and attenuating liver fibrosis. Together, the current findings, substantiated by in vitro and in vivo studies, demonstrate potent antifibrotic capacities of MAPs, marking an essential advancement in lysosome-targeting degradation technology for liver fibrosis treatment and expanding potential therapeutic options for this intractable condition.

Interactions between atrial fibrosis and inflammation in atrial fibrillation

Atrial fibrillation (AF) is a complex arrhythmia driven by intricate pathophysiological mechanisms, with atrial fibrosis and inflammation emerging as central players in its initiation and perpetuation. Key pathways, including the renin-angiotensin-aldosterone system (RAAS), TGF-β/Smad signaling, and pro-inflammatory cytokine cascades (e.g., TNF-α/NF-κB, IL-6/STAT3), contribute to fibrotic remodeling and electrophysiological dysfunction. These pathways promote extracellular matrix deposition, fibroblast activation, and heterogeneous conduction, creating a substrate for AF maintenance. Contemporary therapeutic approaches predominantly target rhythm control via catheter ablation techniques and pharmacological interventions with antiarrhythmic agents. Nevertheless, the efficacy of anti-inflammatory approaches, such as corticosteroids and colchicine, remains uncertain due to limited robust clinical evidence, highlighting the need for further investigation. Advanced fibrosis quantification modalities, particularly late gadolinium-enhanced magnetic resonance imaging and electroanatomic mapping, have emerged as valuable tools for optimizing ablation strategies. Furthermore, emerging evidence highlights significant sex-based disparities in atrial fibrosis distribution and electrophysiological substrate characteristics, suggesting the potential for gender-specific therapeutic approaches. This comprehensive review systematically examines the pathophysiological roles of atrial fibrosis and inflammation in AF progression, with particular emphasis on their intricate bidirectional relationship. Through detailed elucidation of these mechanistic interactions, we aim to facilitate the development of novel therapeutic interventions to enhance clinical management of AF.

Fibrotic extracellular matrix microenvironment induces alveolar type II epithelial cell senescence via integrin-β1/FAK/YAP signaling pathway.

Fibrotic extracellular matrix microenvironment induces alveolar type II epithelial cell senescence via integrin-β1/FAK/YAP signaling pathway.

The lncRNA MIR503HG/miR-16-5p/FOSL1 pathway mediates autophagy to promote esophageal epithelial cells proliferation and EMT in esophageal restenosis.

The lncRNA MIR503HG/miR-16-5p/FOSL1 pathway mediates autophagy to promote esophageal epithelial cells proliferation and EMT in esophageal restenosis.

Luteolin delays the progression of IgA nephropathy by attenuating inflammation, oxidative stress and reducing extracellular matrix accumulation through activating the Nrf-2/HO-1 pathway

IgA nephropathy (IgAN) is the most common primary glomerulonephritis and the main cause of end-stage renal disease (ESRD). Luteolin (Lut), which is present in various plants, has anti-inflammatory and antioxidant properties under numerous medical conditions. This study aimed to investigate the therapeutic effects and potential mechanisms of Lut on IgAN. Mouse models of IgAN and HBZY-1 cells stimulated with Gd-IgA1 were used as experimental objects. Renal pathology, inflammation, reactive oxygen species (ROS) levels, and extracellular matrix (ECM) accumulation were measured. The results indicated that Lut improved renal pathological damage, reduced the levels of inflammatory cytokines, decreased ROS levels, and attenuated ECM accumulation. Moreover, Lut promoted the activation of the Nrf-2/HO-1 pathway. Furthermore, blocking Nrf2 reversed the suppressive effects of Lut on inflammation, oxidative stress, and the expression of ECM proteins in mesangial cells stimulated with Gd-IgA1. In conclusion, the protective effect of Lut against IgAN may occur by triggering the Nrf2/HO-1 pathway, thereby suppressing inflammation, oxidative stress, and ECM deposition.

CXCL12 Drives Reversible Fibroimmune Remodeling in Androgenetic Alopecia Revealed by Single-Cell RNA Sequencing

Androgenetic alopecia (AGA) is a common form of hair loss characterized by androgen-driven tissue remodeling, including progressive follicular miniaturization and dermal fibrosis, which is accompanied by low-grade immune activation. However, the molecular mechanisms underlying this fibroimmune dysfunction remain poorly understood. Dermal fibroblasts (DFs) have been suggested as androgen-responsive stromal cells and a potential source of CXCL12, a chemokine implicated in fibroimmune pathology, but their precise role in AGA has not been fully established. In this study, we performed single-cell transcriptomic profiling of a testosterone-induced mouse model of AGA, with or without treatment of CXCL12-neutralizing antibody, to elucidate the pathological role of CXCL12 in mediating stromal-immune interactions. Our analysis suggested that DFs are the primary androgen-responsive population driving CXCL12 expression. Autocrine CXCL12-ACKR3 signaling in DFs activated TGF-β pathways and promoted fibrotic extracellular matrix deposition. In parallel, paracrine CXCL12-CXCR4 signaling reprogrammed Sox2+Twist1+ dermal papilla cells (DPCs) and promoted the accumulation of pro-fibrotic Trem2+ macrophages, contributing to impaired hair follicle regeneration. Notably, CXCL12 blockade attenuated these stromal and immune alterations, restored the regenerative capacity of DPCs, reduced pro-fibrotic macrophage infiltration, and promoted hair regrowth. Together, these findings identify CXCL12 as a central mediator of androgen-induced fibroimmune remodeling and highlight its potential as a therapeutic target in AGA.

Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis

BackgroundChanges in macrophage function are crucial contributors to hepatic inflammation and fibrosis. However, the role of macrophages in the development of liver fibrosis in dairy cows with ketosis remains unclear. This study integrated proteomics and cytokine array approach to identify the multifactorial and multicellular interaction effects driving liver fibrosis in dairy cows with ketosis and analyze the mechanism by which the proinflammatory shift in macrophages contributes to liver fibrosis.ResultsHistopathological analysis revealed liver injury, including severe steatosis, infiltration of inflammatory cells, an increase in lipid deposition, and a decrease in glycogen expression in ketotic cows. Moreover, the number of mitochondria considerably increased in hepatocytes. The activation of the dynamin-related protein 1/mitochondrial fission factor (DRP1/MFF) pathway induced excessive mitochondrial fission, and the inhibition of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) pathway led to the accumulation of intracellular reactive oxygen species (ROS). Proteomic analysis revealed the activation of extracellular matrix (ECM)-related functions and the NF-κB pathway in the liver, whereas cytokine array analysis revealed that the cytokine network was dysregulated. The accumulation of ROS triggered NF-κB nuclear translocation, inducing a proinflammatory shift in macrophages and liver inflammation. M1 polarization of macrophages promotes the release of proinflammatory mediators, which stimulated hepatic stellate cells (HSCs) activation, leading to ECM deposition, ultimately contributing to liver fibrosis.ConclusionsTo summarize, our study revealed the multifactorial and multicellular interaction effects driving liver fibrosis. Our results preliminarily showed that increased mitochondrial fission and inhibition of the Nrf2/HO-1 pathway are key factors in activating macrophages, which can lead to liver fibrosis in dairy cows with ketosis.

Endothelial sensitivity to pro-fibrotic signals links systemic exposure to pulmonary fibrosis

Pulmonary fibrosis (PF) is a life-threatening condition characterised by excessive extracellular matrix deposition and tissue scarring. While much of PF research has focused on alveolar epithelial cells and fibroblasts, endothelial cells have emerged as active contributors to the disease initiation, especially in the context of systemic exposure to pro-fibrotic substances. Here, we investigate early transcriptomic and secretory responses of human umbilical vein endothelial cells (HUVEC) to subtoxic doses of bleomycin, a known pro-fibrotic agent, and TGF-beta, a key cytokine in fibrosis. Bleomycin exposure induced a rapid and extensive shift in the endothelial transcriptional programme, including signatures of endothelial to mesenchymal transition, cellular senescence, and immune cell recruitment. These findings suggest endothelial cells as early initiators of pro-fibrotic signals, independent of contributions from other cell types. In contrast, TGF-beta effects were limited and transient, indicating its pro-fibrotic action may require another initial stimulus and interplay with other cells like fibroblasts. This study highlights the sensitivity of endothelial cells to pro-fibrotic exposure and provides a blueprint of early pro-fibrotic mechanisms that may operate on organs such as the lungs systemically via the endothelium, emphasising its pivotal role in PF pathogenesis.

Hsp47 drives obesity-associated breast cancer progression by enhancing asporin deposition in adipose tissue

Fibrosis is an important feature of adipose tissue in obese individuals; nevertheless, roles of obesity-associated extracellular matrix (ECM) deposition in breast cancer progression largely remain elusive. Here, we show that expression of Hsp47, a chaperone protein involving collagen secretion, is induced in adipose tissue from obese humans and mice. Adipocyte-specific Hsp47 deletion (Adi-KO) suppresses the high-fat diet (HFD)-induced obesity and mammary tumor progression, accompanied by a reduction in ECM deposition. Matrisome analyses lead to the identification of asporin as a new target of Hsp47 in adipose tissue. Co-immunoprecipitation results confirm that the recruitment of Hsp47 enhances asporin secretion in adipocytes. We further show that knockout of asporin suppresses HFD-induced mammary tumor growth, while exogenous of asporin partially rescues tumor growth in the decellularized mammary gland derived from Hsp47 Adi-KO mice. These results indicate that asporin at least partially mediates Hsp47 function in HFD-associated tumor progression. Digital spatial profiling (DSP) analyses show that Hsp47 depletion significantly increases the accumulation of CD8 T cells in tumor and tumor-associated adipose tissues. These results implicate that Hsp47, along with-it mediated ECM deposition, suppresses the anti-tumor immunity under HFD conditions. These findings reveal Hsp47 as a novel target for mitigating obesity-associated breast cancer progression.

A ROS/ultrasound dual-responsive nanocarrier enhances drug penetration for ameliorating metabolic dysfunction-associated steatohepatitis.

A ROS/ultrasound dual-responsive nanocarrier enhances drug penetration for ameliorating metabolic dysfunction-associated steatohepatitis.

Yoda1 Inhibits TGFβ-Induced Cardiac Fibroblast Activation via a BRD4-Dependent Pathway.

Fibrosis represents a pivotal pathological process in numerous diseases, characterized by excessive deposition of extracellular matrix (ECM) that disrupts normal tissue architecture and function. In the heart, cardiac fibrosis significantly impairs both structural integrity and functional capacity, contributing to the progression of heart failure. Central to this process are cardiac fibroblasts (CFs), which, upon activation, differentiate into contractile myofibroblasts, driving pathological ECM accumulation. Transforming growth factor-beta (TGFβ) is a well-established regulator of fibroblast activation; however, the precise molecular mechanisms, particularly the involvement of ion channels, remain poorly understood. Emerging evidence highlights the regulatory role of ion channels, including calcium-activated potassium (KCa) channels, in fibroblast activation. This study elucidates the role of ion channels and investigates the mechanism by which Yoda1, an agonist of the mechanosensitive ion channel Piezo1, modulates TGFβ-induced fibroblast activation. Using NIH/3T3 fibroblasts, we demonstrated that TGFβ-induced activation is regulated by tetraethylammonium (TEA)-sensitive potassium channels, but not by specific K⁺ channel subtypes such as BK, SK, or IK channels. Intriguingly, Yoda1 was found to inhibit TGFβ-induced fibroblast activation through a Piezo1-independent mechanism. Transcriptomic analysis revealed that Yoda1 modulates fibroblast activation by altering gene expression pathways associated with fibrotic processes. Bromodomain-containing protein 4 (BRD4) was identified as a critical mediator of Yoda1's effects, as pharmacological inhibition of BRD4 with JQ1 or ZL0454 suppressed TGFβ-induced expression of the fibroblast activation marker Periostin (Postn). Conversely, BRD4 overexpression attenuated the inhibitory effects of Yoda1 in both mouse and rat CFs. These results provide novel insights into the pharmacological modulation of TGFβ-induced cardiac fibroblast activation and highlight promising therapeutic targets for the treatment of fibrosis-related cardiac pathologies.

Emerging Biomarker Potential of Extracellular Vesicle-Enclosed MicroRNAs for Liver Fibrosis Detection.

Liver fibrosis is a frequent pathological outcome of long-term liver diseases, arising from sustained damage to the liver. Two main types of liver damage can trigger fibrotic progression: hepatocellular injury, often caused by viral infections, alcohol, or metabolic disorders, and cholestatic injury, associated with impaired bile flow due to autoimmune or congenital conditions. Despite diverse etiologies, liver fibrosis exhibits conserved biological processes, including hepatocyte death, chronic inflammation, disruption of epithelial or endothelial barriers, and excessive deposition of extracellular matrix (ECM) components. These coordinated events reflect the complex interplay among parenchymal damage, immune activation, and fibrogenic signaling pathways. If unresolved, fibrosis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In the pursuit of non-invasive biomarkers for early detection and monitoring of fibrosis, extracellular vesicles (EVs) have garnered significant attention. Among the diverse cargoes within EVs, microRNAs (miRNAs) have emerged as particularly promising due to their stability, disease-specific expression patterns, and involvement in fibrogenic signaling. This review explores the role of EV-associated miRNAs in liver fibrosis, highlighting key candidates implicated in hepatocellular and cholestatic injury and their clinical potential as diagnostic and prognostic biomarkers, with special focus on MAFLD/MASH, primary sclerosing cholangitis, primary biliary cholangitis, and biliary atresia as representatives.

Biohybrid microstructured hydrogels obtained via in situ extracellular matrix deposition and decellularization using supercritical CO2.

In recent decades, our understanding of biomaterials has shifted from seeing them simply as physical supports for cells or drug delivery platforms to recognizing their active and dynamic role in tissue repair, guided by their physicochemical, mechanical, and biological properties. Biologically derived materials such as the decellularized extracellular matrix (dECM) offer the advantage of replicating the biomolecular cellular environment and have been proposed for tissue regeneration. However, their use as scaffolds is hindered by poor mechanical properties and limited tunability of physical features. Herein, we fabricated a bioinspired hybrid hydrogel by integrating a chemically cross-linked microporous polysaccharide scaffold with native ECM directly secreted by cells. First, the scaffold synthesis and culture conditions were optimized to enhance ECM deposition by fibroblasts. To obtain an acellular scaffold, decellularization using supercritical CO2 was performed and compared to a conventional method, demonstrating its superiority in ensuring efficient decellularization while preserving an enriched ECM lining the surface of the pores and preventing scaffold damage. The biohybrid hydrogel was characterized by a very low amount of DNA (< 5 ng DNA /mg) and a network of highly interconnected pores covered by an abundant ECM including collagen I, collagen IV, fibronectin, elastin and laminin. This work presents a new versatile strategy that can be adapted to various tissues to engineer biomimetic microstructured materials overcoming the limitations associated with polymer-based and dECM-based strategies when used independently.

Pericardial adipose tissue promotes transition to heart failure with reduced ejection fraction upon pressure-overload in mice.

In patients, severity of pressure-induced heart failure (HF) due to aortic stenosis and metabolic disorder correlates with thickness and mass of epicardial adipose tissue (EAT). We examined the role of the less studied pericardial adipose tissue (PAT) during manifestation and progression of pressure-induced HF in mice. Progressive remodeling was assessed in C57BL/6J males, aged 9weeks, following sham surgery or transverse aortic constriction (TAC) for 1week (early pressure-overload), 8 (chronic pressure-overload), or 12weeks (HF with reduced ejection fraction, HFrEF) with or without concomitant PAT excision. PAT removal did not affect early (1-week TAC) or chronic (8weeks) pressure-overload-induced concentric remodeling. However, initial PAT excision prevented lung congestion, progressive LV dilation and systolic dysfunction and thereby protected against transition to HFrEF. This protection was associated with alleviation of early TAC-induced pro-inflammatory monocyte and macrophage expansion, attenuation of persistent pro-hypertrophic, pro-inflammatory and pro-fibrotic LV gene expression and the reduction of microscar and perivascular fibrosis in the long term. The latter was reflected by reduced peri-coronary accumulation of pro-fibrotic CD206+ macrophages, and prevention of periostin upregulation. Moreover, PAT protein directly activated naïve cardiac fibroblasts in vitro while bulk RNAsequencing revealed the initiation of an extracellular matrix deposition, monocyte recruiting, and macrophage activation program in the PAT early upon TAC. Our data suggest that PAT does not exert crucial impact on pressure-induced hypertrophy, while its removal counteracts HFrEF manifestation in mice, at least in part, by preventing excessive fibrotic responses suggested to derive from reciprocal fibroblast-macrophage interactions.

CircERC1 facilitates chemoresistance through inhibiting pyroptosis and remodeling extracellular matrix in pancreatic cancer

BackgroundPancreatic ductal adenocarcinoma (PDAC) resists to neoadjuvant treatment even though overall survival (OS) is transiently prolonged while the underlying mechanism of this drug resistance remains elusive.MethodsGemcitabine combined with Nab-paclitaxel (GEM-NabP) treated PDAC tissues-derived EVs were isolated and underwent circRNA sequencing. CircERC1 was identified as an EVs-packaged circRNA that regulates PDAC progression and tumor microenvironment (TME) in vitro and in vivo with the help of EdU, colony formation, SRB viability assays, transwell assays and PET-CT analysis. The underlying mechanism was substantiated by qRT-PCR, Western blot, RNA pull-down, mass spectrometry, RNA immunoprecipitation and Co-immunoprecipitation. In addition, single-cell RNA sequencing was adopted to analyze the TME and immunohistochemistry, dual luciferase reporter assay were performed to validate the results.ResultsCircERC1 biogenesis is activated by QKI after GEM-NabP treatment. It interacts with hnRNPA1 and promotes its ubiquitination degradation by blocking its SUMOylation at K183. The degraded hnRNPA1 fails to upregulate PKM2, a crucial activator of NLRP3 inflammasome, thereby inhibiting Caspase1-GSDMD mediated pyroptosis. Furthermore, EVs-packaged circERC1 enhances extracellular matrix (ECM) deposition and hindering drug and immune cells infiltration in cancer associated fibroblasts (CAFs) in PDAC microenvironment.ConclusionsOur findings reveal a novel circERC1 as a key regulator in PDAC-secreted EVs following paclitaxel (PTX) treatment, thereby inhibiting gemcitabine/Nab-paclitaxel (GEM-NabP) induced pyroptosis. Our results highlight a potential therapeutic target for overcoming chemoresistance and remodeling pancreatic TME.

Cordycepin ameliorates high glucose-induced proliferation, inflammation, and extracellular matrix deposition in glomerular mesangial cells through Smad7-dependent manner.

Cordycepin ameliorates high glucose-induced proliferation, inflammation, and extracellular matrix deposition in glomerular mesangial cells through Smad7-dependent manner.

Systematic Review of the Differential Effects of TGF-β1 in Ischemic and Hemorrhagic Preclinical Stroke Models.

Stroke is a leading cause of death, with patients often experiencing significant disability. Stroke is classified as ischemic, caused by the occlusion of a blood vessel leading to reduction in cerebral blood flow, or hemorrhagic, resulting from the rupture of a vessel that causes bleeding into the brain. Transforming growth factor β1 (TGF-β1), a pleiotropic cytokine, has been investigated in stroke due to its diverse effects on proliferation, extracellular matrix deposition, and inflammation. This systematic review examined the role of TGF-β1 in preclinical studies of ischemic and hemorrhagic stroke. A search of PubMed, Web of Science, and Scopus databases identified animal studies examining TGF-β1 signaling as an outcome or intervention. A total of 89 studies were included: 68 on ischemic stroke and 21 on hemorrhagic stroke. Studies were assessed for bias following the SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation) guidelines, followed by extraction of methodology and the role of TGF-β1. Compliance with SYRCLE guidelines was found to be low, and the methodological approaches to stroke models were variable. A range of interventions were shown to modify TGF-β1 expression or signaling, with exogenous TGF-β1 improving outcomes in all ischemic stroke studies. TGF-β1 was found to play a protective role in 76% of ischemic stroke studies but was only protective in 33% of hemorrhagic stroke studies, with likely involvement in fibrosis development in the latter. Our findings suggest a marked difference in TGF-β1 function between these types of stroke, and it is hypothesized that blood cytotoxicity following hemorrhagic stroke may generate more sustained TGF-β1 expression than that seen in ischemic stroke. This may lead to TGF-β1-mediated fibrosis and hydrocephalus, as opposed to the neuroprotective role played by the same molecule following ischemic stroke. These findings highlight the possible clinical utility of exogenous TGF-β1 therapies after ischemic stroke, and TGF-β1 inhibitors after hemorrhagic stroke, to reduce morbidity and disability caused by these events.

SESN3 restrains the progress of idiopathic pulmonary fibrosis by targeting the activity of FOSL2

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive macrophage infiltration and extracellular matrix deposition. The progress of IPF is promoted by M2 macrophages which produce pro-fibrotic factors and induce fibroblast differentiation. SESN3 was upregulated in lung tissues of IPF patients and mice with bleomycin-induced pulmonary fibrosis. However, the role of SESN3 in IPF and its related mechanisms remain largely unknown.MethodsHere, we used IL-4/13 to induce macrophage M2 polarization in RAW264.7 cells and constructed a mouse model of pulmonary fibrosis by intratracheal injection of bleomycin. Adenoviruses targeting SESN3 were constructed to infect RAW264.7 cells and BLM-induced mice to assess the function of SESN3 in macrophage M2 polarization in the progress of IPF and mRNA-seq and Co-IP-MS analysis were performed to find the downstream factors.ResultsFor in vitro experiments, SESN3 knockdown promoted the M2 polarization level, the release of pro-fibrosis factors and the activation of fibroblast, overexpression of SESN3 had an opposite trend. For in vivo experiments, the increased degree of pulmonary fibrosis in BLM mice was relieved after overexpression of SESN3. Meanwhile, overexpression of SESN3 repressed the increased macrophage M2 polarization level induced by BLM. Mechanically, FOSL2 was screened out through mRNA-seq and Co-IP-MS analysis due to its binding affinity with SESN3 and the observed downregulation of its downstream pro-fibrotic factor expression. The expression of FOSL2 in the nucleus was down-regulated after SESN3 overexpression. Under IL-4/13 treatment, the increased levels of macrophage M2 polarization and pro-fibrotic factors induced by SESN3 knockdown was recovered after knocking down FOSL2 in RAW264.7 cells.ConclusionIn summary, our study suggested that SESN3 regulated the IPF process through inhibiting macrophage M2 polarization by targeting the activity of FOSL2.

Spatial transcriptomics and multi-omics reveal relapse and resistance mechanisms of EndMT-derived CAFs mediated by TNC and FLNC in glioblastoma

BackgroundChemoresistance and recurrence following treatment are the greatest impediments to the prognosis of glioblastoma (GBM). Increasing evidence indicates that cancer-associated fibroblasts (CAFs) play a significant role in the progression of glioblastoma. Nevertheless, the role and source of CAFs in recurrent and chemotherapy-resistant GBMs still remain ambiguous.MethodsSpatial transcriptome (ST) sequencing was conducted on the tissue microarray encompassing primary and recurrent glioma samples in order to characterize the cellular composition. Subsequently, the infiltration of CAFs in our formerly established in vivo temozolomide (TMZ)-resistant model was inspected through immunohistochemical staining. Additionally, we carried out RNA-seq and label-free quantitation (LFQ) proteomics on HCMECs co-cultured with TMZ-sensitive (TMZ-S) or TMZ-resistant (TMZ-R) cells to explore the mechanism.ResultsThis investigation revealed that CAFs and astrocytes are enriched in recurrent GBM, and this phenotype is associated with the expression of extracellular matrix (ECM) proteins associated with COL1A1 and FN1 deposition. Further investigations revealed that tenascin-C (TNC) and filamin C (FLNC), which potentially mediate endothelial-to-mesenchymal transition (EndMT), are the predominant factors that induce the deposition of ECM proteins in the resistance-promoting microenvironment. Additionally, the natural product punicalin (PNC) was found to downregulate EndMT-related proteins, multidrug resistance-associated membrane proteins, and collagen-related proteins by targeting TNC and FLNC, thereby increasing the susceptibility of temozolomide (TMZ)-resistant cells to chemotherapeutic agents both in vitro and in vivo.ConclusionThese discoveries indicate that TNC and FLNC induced EndMT was a key resource of CAFs and targeting TNC and FLNC to inhibit EndMT and the collagen pathway is a promising tactic for reversing drug resistance in tumours. The development of combined chemotherapeutic strategies based on the features of tumour microenvironment endothelial cells and ECM deposition has high potential clinical value in increasing the efficacy of tumour treatment.

DNMT3B aggravated renal fibrosis in diabetic kidney disease via activating Wnt/β-catenin signaling pathway

The incidence of diabetic kidney disease (DKD) has increased rapidly worldwide in recent decades, and DKD is the leading cause of chronic kidney disease. The Wnt/β-catenin pathway is widely recognized as a critical contributor to DKD. However, how this pathway is activated in DKD is still unknown. Recent studies have revealed that epigenetic mechanisms play key roles in DKD. DNA methylation is an epigenetic mechanism that is essential for regulating gene transcription. Here, we demonstrated that reducing the expression of DNMT3B, a DNA methyltransferase, markedly decreased extracellular matrix (ECM) deposition and diabetic renal fibrosis (DRF). Furthermore, we found that DNMT3B activated the Wnt/β-catenin pathway by suppressing SFRP5 expression in HG-induced renal tubular epithelial cells. Mechanistically, we observed that DNMT3B increased the promoter methylation levels of sfrp5, which contributed to a decrease in SFRP5 protein expression. Additionally, Pharmacological disruption of DNA methylation (via 5-Aza) and genetic knockdown of DNMT3B suppressed the Wnt/β-catenin pathway, leading to the attenuation of ECM deposition and DRF. Thus, our study provides a novel understanding of the epigenetic regulation of DKD pathogenesis and a new therapeutic strategy for DKD by disrupting the Wnt/β-catenin pathway.