Search Results (82)

Fibrosis emerges when normally self-limiting tissue repair fails to resolve and overlapping phases of injury, stromal activation, extracellular matrix (ECM) deposition and remodelling become sustained. MicroRNAs (miRNAs) shape this transition by coordinating signalling, cell-state and matrix programmes. Functionally, pro-fibrotic fibro-miRs amplify fibrogenic pathways, whereas anti-fibrotic miRNAs restrain fibroblast activation and ECM production; the miR-29 family is a principal member of the latter group. This review examines miR-29 family organisation, the regulation of miR-29b by transforming growth factor-β (TGF-β)/Smad and additional transcriptional and inflammatory inputs, and the molecular targets through which miR-29b controls collagen synthesis, processing and crosslinking. Direct canonical targets are distinguished from experimentally supported, predicted and indirect pathway components. Evidence is evaluated across fibroblasts and myofibroblasts, epithelial and endothelial cells, and pulmonary, hepatic, renal, cardiac, dermal and ocular fibrosis models. Therapeutic translation is considered in relation to miR-29b mimics and agomirs, local and tissue-targeted delivery, pharmacokinetics, dose control, off-target repression, immune activation and long-term safety. Overall, miR-29b remains a credible network-level anti-fibrotic candidate, but successful translation requires cell- and disease-specific target validation, selective delivery and preservation of physiological wound repair. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate below 10%. Cancer-associated fibroblasts (CAFs) promote epithelial–mesenchymal transition (EMT) and metastasis, yet the specific CAF subtypes and molecular axes driving PDAC progression remain incompletely understood. Here, using multi-omics data from PDAC samples, we identified a malignant ductal subpopulation, termed Ductal-T0, characterized by the highest EMT activity and prominent acquisition of myofibroblastic CAF (myCAF)-like transcriptional programs. Computationally, we predicted that myCAF-secreted THBS2 and FN1 engage the ITGA3/ITGB1/SDC1/SDC4 receptor axes in Ductal-T0 cells, which could activate TNF, NF-κB, TGF-β, and PI3K-AKT-signaling pathways to promote EMT. Pseudotime trajectory and velocity analyses suggested that Ductal-T0 cells exhibited the highest propensity to acquire myCAF-like features among all ductal subpopulations. Survival analysis revealed that an increased proportion of Ductal-T0 cells and elevated abundance of THBS2-ITGA3/ITGB1 and THBS2-SDC1 ligand–receptor pairs were significantly associated with poor prognosis. Spatial transcriptomics further revealed that myCAFs and Ductal-T0 cells co-localized at the tumor margin, which may contribute to reduced immune cell presence via dense extracellular matrix (ECM) barrier formation—a computationally inferred model of EMT-associated immune exclusion and metastatic progression—and identify THBS2 as a promising candidate for future therapeutic investigation to disrupt CAF–tumor crosstalk in PDAC. Full article

Obesity is associated with chronic adipose dysfunction characterized by oxidative stress, inflammation, senescence, and fibrosis, which can promote tumor progression. In prostate cancer, periprostatic adipose tissue may directly influence the prostate microenvironment. Radiation therapy is widely used in prostate cancer, but radiation-induced adipose dysfunction in obesity and its impact on the prostate microenvironment remain poorly understood. In the present study, we investigated the impact of obese and irradiated obese adipose microenvironments on prostate stromal remodeling, as well as the activation of prostate fibroblasts mediating prostate cancer progression. We utilized a high-fat diet obesity model with localized adipose irradiation in animal and in vitro studies using obese and irradiated obese adipocytes. Prostates from obese and irradiated obese mice exhibited epithelial hyperplasia, increased stromal activation markers, oxidative damage, and senescence. Interestingly, radiation maintained the obesity-induced pathological behavior in the prostate, rather than elevating it. The conditioned media from obese and irradiated obese adipocytes induced stromal activation markers, senescence, extracellular H₂O₂ production, pro-survival signaling, and inflammation. Notably, the only significant changes observed with the addition of radiation to obesity were enhancement of fibrosis-associated features and infiltration of CD4⁺ T cells. Functionally, prostate myofibroblasts or senescent fibroblasts promoted prostate cancer migration and induced epithelial-to-mesenchymal transition and elevated pro-tumorigenic pathways. Cytokine profiling identified elevated levels of CXCL10 and CXCL11 from myofibroblasts, and pharmacological inhibition of CXCR3 significantly reduced prostate cancer migration, implicating this signaling axis in activated fibroblast-driven tumor-promoting crosstalk. Collectively, these findings demonstrate obesity-associated adipose dysfunction reprograms the prostate microenvironment toward a pro-tumorigenic state, while radiation sustains rather than markedly amplifies these pathological changes, identifying obese adipose-stromal crosstalk and the CXCL10/CXCL11-CXCR3 axis as potential therapeutic targets to inhibit prostate cancer progression. Full article

Background: Glaucoma filtration surgery (GFS) is performed to slow down disease progression in glaucoma, a leading cause of irreversible blindness worldwide. Following surgery, pathological wound healing may lead to conjunctival fibrosis and filtering failure. Myofibroblast transition of human Tenon’s fibroblast (HTF) is responsible for postoperative conjunctival scarring, with TGFβ signalling playing a key role in this process. However, the detailed molecular mechanism underlying myofibroblast transition in HTF remain understudied. Methods: In this study, we performed transcriptomic analysis to delineate the TGFβ1-induced changes in the transcriptome of HTF. HTF was isolated from three patients following GFS and treated with TGFβ1 for 5 days, followed by RNA-seq for transcriptomic profiling. Results: Our results identified 3362 differentially expressed genes (DEGs) in HTF following TGFβ1 treatment, of which 1532 were upregulated and 1820 were downregulated. Using gene ontology analysis, we identified signalling pathways associated with the pathogenesis of conjunctival fibrosis, including pathways involved in myofibroblast differentiation, TGFβ-signalling, collagen and extracellular matrix organisation, epithelial to mesenchymal transition, and cell cycle regulation. This study provided detailed characterisation of the transition from HTF to myofibroblast, and highlighted key genes that are upregulated (LDLRAD4, CDKN2B, FZD8, MYOZ1) and downregulated (SOD3, LTBP4 and RCAN2) in this myofibroblast transition process. Conclusions: Overall, this study provided insights into the transcriptional landscape of HTFs and myofibroblast differentiation, which has important implication to understanding the pathophysiology of conjunctival scarring and development of new therapeutic agents. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial lung disease characterized by excessive extracellular matrix (ECM) accumulation, disruption of lung architecture, and progressive loss of pulmonary function. IPF is frequently accompanied by comorbid conditions that exacerbate disease progression and negatively impact prognosis. To address the biological complexity of IPF, this study presents a comprehensive molecular systems architecture that enables a system-level understanding of biomolecular interactions within the fibrotic lung microenvironment in response to external and physiological triggers. Methods: A literature search is conducted using the Medical Subject Headings (MeSH) keywords in PubMed and MEDLINE to identify relevant peer-reviewed articles published from April 2008 to June 2025, with Google Scholar used solely to retrieve full-text versions of articles identified through this search. The systems biology tool CytoSolve^® was used to perform the systematic review and to support the curation and development of the molecular systems architecture of IPF pathogenesis. Full-length articles that contained Medical Subject Headings keywords relevant to IPF pathogenesis were selected for a comprehensive review. A total of 150 studies published between April 2008 and June 2025 met the inclusion criteria and were included in the systematic analysis. This systematic review was not registered. Results: Findings were synthesized qualitatively into a multilayered molecular interactome rather than through statistical meta-analysis. The architecture integrates interactions across sixteen lung-associated cell types, including epithelial, endothelial, mesenchymal, immune, and stromal populations. Key external triggers—such as bleomycin (BLM), asbestos, silica, radiation, cigarette smoke, Herpes virus, and genetic mutations (SFTPC I73T), along with hypoxia associated with comorbidities—initiate coordinated cellular responses that converge on three fundamental pathological processes: inflammation, myofibroblast differentiation, and tissue remodeling. These interconnected processes collectively drive the initiation and progression of IPF. Conclusions: This molecular systems architecture unifies triggers, cellular components, molecular pathways, and biological processes into a multilayered framework for identifying therapeutic targets, biomarkers, and rational single- and combination-treatment strategies in IPF. Full article

Tubulointerstitial fibrosis (TIF) represents the final common pathway leading to end-stage renal disease (ESRD) in chronic kidney disease (CKD). Despite fibrosis being well established as a key pathological hallmark, the molecular mediators that drive this process remain incompletely understood. BPI fold-containing family A member 2 (BPIFA2), a secreted innate immune protein of the sPLUNC family, was upregulated in renal tubular epithelial cells across diverse CKD etiologies and strongly correlated with collagen I accumulation and TIF severity. Tubule-specific knockdown of BPIFA2 significantly alleviated renal histopathological injury and fibrosis, whereas exogenous BPIFA2 administration aggravated fibrotic progression. Mechanistically, BPIFA2 promoted epithelial–mesenchymal transition (EMT) in tubular epithelial cells and triggered macrophage-to-myofibroblast transition (MMT) associated with the TGF-β/Smad3 signaling pathway. In conclusion, our findings identify BPIFA2 as a novel profibrotic mediator in CKD. Targeting BPIFA2 or its downstream signaling may offer new therapeutic opportunities for chronic kidney disease. Full article

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with renal fibrosis as its core pathological hallmark. A central driver of this fibrosis is epithelial–mesenchymal transition (EMT), during which renal tubular epithelial cells transform into matrix-producing myofibroblasts. Endothelial–mesenchymal transition (EndMT) has also emerged as a critical contributor, and together with EMT, accounts for the progressive accumulation of myofibroblasts and extracellular matrix. A major clinical challenge in halting DKD progression is “metabolic memory”, a phenomenon whereby renal injury persists and EMT/EndMT remain activated even after glycemic control is achieved. The molecular basis underlying this sustained activation remains incompletely understood. Emerging evidence indicates that metabolic memory is largely mediated by epigenetic mechanisms, including histone modifications, DNA methylation, and non-coding RNA dysregulation. These stable epigenetic imprints maintain the persistent activation of key pro-fibrotic signaling pathways, especially TGF-β, thereby continuously driving EMT, EndMT, and excessive extracellular matrix deposition. Although targeting epigenetic regulators has shown promising anti-fibrotic effects, a systematic review that integrates how metabolic memory orchestrates both EMT and EndMT through a multi-layered epigenetic network remains lacking. This review comprehensively summarizes the epigenetic mechanisms by which metabolic memory sustains EMT and EndMT in DKD, highlights key therapeutic targets, and discusses their translational and clinical implications. Full article

Background: The rising incidence of CINIII, particularly in younger patients, has highlighted limitations of current surgical treatments, which can affect fertility and carry recurrence risks. This underscores an urgent clinical need for non-invasive therapies. Our study addresses this by investigating the cellular and molecular changes during CINIII progression to cervical squamous cell carcinoma (CSCC). Methods: We employed single-cell sequencing to meticulously analyze cell types and molecular mechanisms within cervical epithelial cells and their microenvironment throughout the CINIII-to-CSCC transition. Results: Key findings include the identification of Sox2 and its signaling pathway as markers for specific cervical stem cells (CCSCs) during malignant transformation. In the microenvironment, upregulated VWF, MMP2, and HTRA1 were observed in vascular endothelial cells, while TXNIP+ and ARL4D+ fibroblasts underwent transformation into myofibroblasts. Immune cell proportions notably increased, particularly macrophages, T cells, B cells, NK cells, mast cells, and neutrophils, contrasting with a decrease in non-immune cells. Furthermore, interaction analysis revealed that communication between macrophages and cervical epithelial cells was the most prominent. Conclusions: This research comprehensively details the complex cellular and molecular remodeling inherent in CINIII progression. By pinpointing specific pathways and cell populations, our findings establish a crucial framework for developing innovative, non-invasive drug therapies to delay disease progression and ultimately improve long-term reproductive outcomes for patients. Full article

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) represents a dynamic and multistage pathological process driven by maladaptive intercellular communication. Rather than resulting from isolated cellular injury, AKI-CKD progression unfolds through a spatially and temporally coordinated dysregulation of cellular networks. In the acute phase, damaged tubular epithelial cells act as instigators, releasing damage-associated molecular patterns (DAMPs) and activating a storm of inflammatory crosstalk among immune cells, endothelium, and fibroblasts. During the subacute repair phase, imbalance in macrophage polarization (M1 persistence/M2 dysfunction) and the emergence of senescent tubular cells with a senescence-associated secretory phenotype (SASP) together create a pro-fibrotic microenvironment. In the chronic phase, activated myofibroblasts—derived from multiple sources—establish self-sustaining feedback loops via autocrine signaling, mechanical memory from the stiffened extracellular matrix (ECM), and ongoing dialogue with immune and resident cells, ultimately leading to irreversible fibrosis. Current therapeutic strategies focused on single molecular targets often fail to disrupt this resilient network homeostasis. Therefore, we propose a paradigm shift toward spatiotemporally precise network-remodeling therapies, which require integrated use of liquid biopsy-based staging, smart nanocarriers for cell-specific delivery, and AI-powered multi-omics modeling. This review systematically delineates the evolving cell-to-cell communication networks across AKI-CKD continuum and highlights innovative strategies to intercept disease progression by targeting the pathophysiology of cellular crosstalk. Full article

Currently, there is no curative medication for idiopathic pulmonary fibrosis (IPF), and therapeutic interventions for IPF are hindered by limited efficacy and severe adverse side effects. Far Infrared Radiation (FIR), an invisible form of electromagnetic energy, has garnered increasing attention for its multiple biological effects. However, its therapeutic benefits and the underlying mechanisms of IPF have not been investigated. In the present study, we established a mouse model of bleomycin-induced pulmonary fibrosis (BIPF) to assess the efficacy of FIR in attenuating BIPF. The results showed that FIR therapy significantly improved the general condition of the mice and protected pulmonary function by ameliorating lung fibrosis, collagen deposition and excessive inflammation. Moreover, FIR could alleviate fibroblast-to-myofibroblast differentiation (FMD), the epithelial–mesenchymal transition (EMT) and angiogenesis in BIPF mice. These beneficial effects were notable both in the pro-fibrotic inflammatory stage and the following fibrotic stage. Mechanistically, FIR exerted anti-inflammatory and anti-fibrotic effects through modulating the p53/TGF-β signaling pathway. Overall, this study elucidates the anti-fibrotic activity and the potential molecular mechanisms of FIR in treating BIPF, providing a therapeutic strategy of convenient, non-invasive physical therapy for alleviating IPF. Of greater significance, the findings of this study display the promising future applications of FIR in managing the physiopathology of various chronic diseases. Full article

Myofibroblasts derived from retinal pigment epithelial (RPE) cells play a key role in the pathogenesis of retinal fibrotic conditions such as proliferative vitreoretinopathy (PVR). Upon exposure to growth factors and cytokines such as TNF-α and TGF-β (TNT), RPE cells undergo epithelial-mesenchymal transition and subsequent transdifferentiation to contractile myofibroblasts. In this study, the effects of JD5037, a peripherally restricted CB1 antagonist, on myofibroblast transdifferentiation of primary cultures of human RPE cells were assessed. JD5037 significantly reduced TNT-induced, RPE cell-mediated collagen gel contraction, an indicator of myofibroblast function, in a concentration-dependent manner. Western blot analysis showed that JD5037 attenuated TNT-induced expression of α-SMA and fibronectin, two molecular markers of myofibroblasts. Furthermore, siRNA knockdown of CB1 cannabinoid receptor partially inhibited TNT-induced myofibroblast transdifferentation of human RPE cells and eliminated the inhibitory effects of JD5037 on myofibroblast transdifferentiation. These data demonstrate, for the first time, that peripherally restricted antagonists, such as JD5037, targeting the CB1 cannabinoid receptor have therapeutic potential for PVR and other retinal fibrotic conditions. Full article

Single-cell RNA-sequencing has transformed our understanding of alveolar epithelial type 2 (AT2) cells and alveolar lipofibroblasts (LIFs) during lung injury and repair. Both cell types undergo dynamic transitions through intermediate states that determine whether the lung proceeds toward regeneration or fibrosis. Emerging evidence highlights reciprocal paracrine signaling between AT2/AT1 transitional cells and LIF-derived myofibroblasts (aMYFs) as a key regulatory axis. Among these, amphiregulin (AREG)–EGFR signaling functions as a central profibrotic pathway whose inhibition can restore alveolar differentiation and repair. The human WI-38 fibroblast model provides a practical platform to study the reversible LIF–MYF switch and screen antifibrotic and pro-regenerative compounds. Candidate therapeutics including metformin, haloperidol and FGF10 show promise in reprogramming fibroblast and epithelial states through metabolic and signaling modulation. Integrating WI-38-based assays, alveolosphere co-cultures, and multi-omics profiling offers a translational framework for identifying interventions that halt fibrosis and actively induce lung regeneration. This review highlights a unifying framework in which epithelial and mesenchymal plasticity converge to define repair outcomes and identifies actionable targets for promoting alveolar regeneration in chronic lung disease. Full article

Intestinal fibrosis is a common complication of inflammatory bowel diseases (IBD), and, to date, effective and safe antifibrotic drugs are still lacking. Emerging evidence suggests that probiotics may provide novel strategies to counteract fibrotic processes. In this study, we evaluated the anti-fibrotic potential of a multi-strain probiotic formulation, OxxySlab^TM, using in vitro models of intestinal fibrosis and epithelial-to-mesenchymal transition (EMT). Human intestinal fibroblasts (CCD-18Co cell line) and epithelial cells (Caco-2 cell line, IECs) were stimulated with transforming growth factor-β1 (TGF-β1) to induce fibrotic and EMT phenotypes, respectively. Treatment with OxxySlab modulated cell proliferation and fibrosis-related markers, which we assessed through CCK-8 assay, Western blotting, and immunofluorescence. The probiotic lysate inhibited both canonical and non-canonical TGF-β1 signaling pathways, and it also reduced TGF-β1 gene expression in activated myofibroblasts, as shown by RT-qPCR. Furthermore, probiotic treatment reversed EMT features by restoring epithelial markers and downregulating mesenchymal markers. These findings highlight the beneficial effects of the multi-strain probiotic formulation as an adjunctive therapeutic agent targeting key pathways involved in intestinal fibrosis. Full article

CD44, a multi-isoform adhesion receptor for hyaluronic acid (HA), plays a crucial role in regulating cell interactions with the extracellular matrix, cell migration, differentiation, and survival in both physiological and pathological contexts. Accumulating experimental evidence suggests that CD44 is not merely a passive marker of mesenchymal cell activation but rather an active signaling hub driving fibrosis in many organs, including the lung, skin, heart, and liver. Its involvement in fibroblast differentiation into myofibroblasts, as well as induction of the invasive phenotype of these cells, shows striking analogies to the mechanisms of epithelial-to-mesenchymal transition (EMT) known from cancer progression. In this paper, we discuss both the molecular mechanisms of CD44-dependent signaling (including through EGFR, MAPK/ERK, CaMKII, lipid rafts, and Smad) and the influence of its modulation (knockout, antibodies, blockade of HA synthesis) on the course of fibrosis in in vitro and in vivo models. In addition, we present the influence of environmental pollutants—such as heavy metals, particulate matter, endocrine disruptors, and microplastics—on the activation of the HA-CD44 axis in connective tissue, with particular emphasis on their role in the induction of chronic inflammation, EMT, and extracellular matrix deposition. The collected evidence suggests that CD44 serves as a central integrator of inflammatory and fibrogenic signals, and its pharmacological modulation may represent a novel therapeutic strategy for treating fibrotic diseases and chronic inflammatory conditions. Full article

Cancer-associated fibroblasts (CAFs) are crucial regulators of the tumor microenvironment (TME), promoting cancer progression, immune suppression, and therapy resistance. Single-cell transcriptomics has identified at least five distinct CAF subtypes: myofibroblastic (myCAFs), inflammatory (iCAFs), antigen-presenting (apCAFs), metabolic (meCAFs), and vascular/developmental (vCAFs/dCAFs), each with unique localization, signaling, and functions. While CAFs are well studied in epithelial cancers, their roles in sarcomas are less understood despite the shared mesenchymal origin of tumor and stromal cells. This overlap blurs the line between malignant and non-malignant fibroblasts, raising fundamental questions about the identity of CAFs in mesenchymal tumors. In this narrative review, we explore the heterogeneity and plasticity of CAFs across solid tumors, focusing on their role in immune evasion, epithelial-to-mesenchymal transition (EMT), and resistance to chemotherapy, targeted therapy, and immunotherapy. We highlight emerging evidence on CAF-like cells in sarcomas and their contribution to tumor invasion, immune exclusion, and metastatic niche formation. We also assess new strategies to target or reprogram CAFs and suggest that CAF profiling may serve as a potential biomarker for patient stratification. Understanding CAF biology across various tumor types, including those with dense stroma and immunologically cold sarcomas, is crucial for developing more effective, personalized cancer treatments. Full article