bims-fibdiv 2026-01-04 papers

bims-fibdiv

Biomed News

on Fibroblast diversity

Issue of 2026–01–04
twenty-two papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary

Provoking myofibroblast death: Strategies to resolve fibrosis and remodel tumor microenvironment.
PLK1 Inhibition by Volasertib Suppresses Key Transcriptional Regulators Underlying Fibroblast Activation and Pulmonary Fibrosis.
Osteopontin aggravates myocardial fibrosis by promoting phenotypic transition of cardiac fibroblasts via Hippo-YAP pathway.
Identification of novel fibroblast subsets in diffuse cutaneous systemic sclerosis.
ORM2 alleviates pancreatic fibrosis in chronic pancreatitis by modulating autophagy via ZG16.
Single-cell profiling reveals lineage-specific fibroblast stromal subtypes drive ECM remodeling and immune modulation in the hepatocellular carcinoma tumor microenvironment.
Roles of Exosome-derived Non-coding RNA in Fibrosis.
Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential.
HMCN1 as a conserved biomarker of epithelial-mesenchymal transition: a cross-cancer analysis.
Transcriptional responses to DHA-induced lipid droplet accumulation in primary adherent mantle cells of Sinonovacula constricta (Lamarck, 1818).
Synthesis and radiolabelling strategies of fibroblast activation protein ligands: a review.
A transcriptomic atlas at bulk and single-cell levels identifies novel transcriptional and splicing regulators of ECM homeostasis in osteoarthritis.
Astragaloside IV: A multipotent phytochemical for treating fibrotic diseases (Review).
Signalling pathways in hepatocellular carcinoma (HCC) metastasis and invasion: Molecular mechanisms and therapeutic implications.
Regulation of Tissue Regeneration by Immune Microenvironment-Fibroblast Interactions.
TAGLN: a stiffness-driven prognostic biomarker for metastatic colorectal cancer.
Emerging epigenetic modifications in renal fibrosis: From mechanisms to treatments.
Fibrin hydrogel incorporated with microspheres containing vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) accelerated the healing of diabetic wounds in rats.
[The extracellular matrix of senescent stromal cells decreased secretion of SDF-1 and HGF by endothelium.]
LncRNA ZFHX4-AS1 initiates an oncogenic axis involving a ZFHX4/SOX2 positive feedback loop to accelerate glioma progression.
Proteoglycans in Prostate Cancer Progression and Therapy Resistance.
Xiangpi Shengji Ointment Accelerates Anal Fistula Healing by Regulating Macrophage-Fibroblast Crosstalk Through the Nuclear Factor Kappa B/Hypoxia-Inducible Factor Alpha/Vascular Endothelial Growth Factor Signaling Axis.

World J Clin Oncol. 2025 Dec 24. 16(12): 111086

Provoking myofibroblast death: Strategies to resolve fibrosis and remodel tumor microenvironment.

Thangavelu Shalini, Ganapasam Sudhandiran.

  Fibrosis is marked by the excessive accumulation of extracellular matrix (ECM) components, leading to tissue scarring and progressive loss of organ function. Myofibroblasts, which emerge during tissue repair, are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells. Their expression of α-smooth muscle actin facilitates contractile activity, while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression. Beyond ECM production, myofibroblasts play a significant role in the tumor microenvironment (TME) of various solid tumors. The TME is a complex network of immune cells, blood vessels, ECM components, and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells, thereby influencing tumor growth, progression, and therapy responsiveness. Through these interactions, myofibroblasts modulate inflammation, angiogenesis, and tissue remodeling. Maintaining myofibroblast homeostasis is therefore crucial, as its disruption can drive the onset of chronic fibrotic conditions and malignancies. This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models, including hypertrophic scar, idiopathic pulmonary fibrosis, oral submucous fibrosis, cardiac fibrosis, and the desmoplastic stroma of pancreatic and breast cancers.

Keywords:  Cancer-associated fibroblasts; Extracellular matrix remodeling; Fibroblast activation; Fibrosis resolution; Mechanotransduction in fibrosis; Myofibroblast apoptosis; Tumor microenvironment

DOI:  https://doi.org/10.5306/wjco.v16.i12.111086
Am J Physiol Lung Cell Mol Physiol. 2026 Jan 02.

PLK1 Inhibition by Volasertib Suppresses Key Transcriptional Regulators Underlying Fibroblast Activation and Pulmonary Fibrosis.

Priyanka Singh, Pradeep Kumar Patel, Rajesh K Kasam, Ryan Lawson, Harshavardhana Haresamudram Ediga, Anil G Jegga, Satish K Madala.

  Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease marked by aberrant fibroblast activation, resulting in excessive proliferation, survival, and accumulation of extracellular matrix (ECM). A critical barrier to developing effective therapies for IPF is the limited understanding of druggable molecular regulators that control fibroblast activation. In this study, we identify the proto-oncogene MYCN as a key driver upregulated in dysregulated fibroblasts from IPF lungs. Mechanistically, we show that TGFα induces MYCN expression via the profibrotic transcription factor Wilms tumor 1 (WT1). Notably, the knockdown of MYCN significantly attenuated fibroblast proliferation, survival, and ECM production. We further show that MYCN positively regulates the mitotic kinase, Polo-like kinase (PLK1), and that pharmacological inhibition of PLK1 using volasertib reduced expression of MYCN, WT1, and PLK1 and mitigated fibroblast activation. In vivo, volasertib treatment attenuated fibroblast activation and collagen deposition during TGFα-induced pulmonary fibrosis. Together, these findings identify a pathogenic role for the WT1-MYCN-PLK1 axis in fibroblast activation and provide proof-of-concept evidence supporting PLK1 inhibition with volasertib as a potential therapeutic strategy for IPF.

Keywords:  Fibroblasts; Idiopathic pulmonary fibrosis; MYCN proto-oncogene; Polo-like kinase 1; Volasertib

DOI:  https://doi.org/10.1152/ajplung.00204.2025
Biochim Biophys Acta Mol Basis Dis. 2025 Dec 30. pii: S0925-4439(25)00500-9. [Epub ahead of print] 168150

Osteopontin aggravates myocardial fibrosis by promoting phenotypic transition of cardiac fibroblasts via Hippo-YAP pathway.

Chen Liu, Wentao Liu, Yuan Wang, Chengzhi Jiang, Sheng Chen, Qianqian Huang, Xiaowei Xiong, Li Wang, Guohua Zeng, Qiren Huang.

  Osteopontin (OPN), a glycosylated protein ubiquitously in cellular matrix, exhibits a low expression in normal myocardial tissue but a high expression in fibrotic myocardial tissue. However, the action and mechanisms of OPN on the pathogenesis of myocardial fibrosis (MF) remain unclear. The purpose of the study is to investigate the action and mechanisms of OPN on the occurrence and development of MF, emphasizing abnormal activation of cardiac fibroblasts (CFs) and extracellular matrix (ECM) deposition. Both NIH-3T3 cells and C57BL/6 J mice were infected with OPN over-expression adenoviruses (Ad-Spp1). Cardiac function and fibrosis degree were evaluated in the presence and absence of angiotensin (AngII) (in vitro) or isoprenaline (ISO) (in vivo). Our data demonstrate that OPN over-expression results in myocardial injury and ECM accumulation under the physiological condition. Moreover, it exacerbates such effects under the pathological condition induced by AngII or ISO; in contrast, OPN knockdown attenuates the fibrotic response in vitro induced by AngII. Interestingly, OPN significantly promotes phenotypic conversion of CFs, characterized as elevated levels of α-SMA and Vimentin, with remarkable proliferation and migration in myocardial tissue. Mechanistically, our data indicate that such effects of OPN are mediated by nuclear translocation of YAP/TAZ via Hippo-YAP pathway, dependent of the membrane receptor integrin αVβ3. Overall, OPN plays significant roles in the phenotypic transition of CFs via integrin-Hippo-YAP axis, ultimately leading to MF. The findings highlight the novel mechanisms of OPN triggering MF and would offer an early marker and potential targets for the prevention and treatment of MF.

Keywords:  Extracellular matrix; Hippo-YAP signaling; Integrin; Myocardial fibrosis; Osteopontin

DOI:  https://doi.org/10.1016/j.bbadis.2025.168150
Ann Rheum Dis. 2025 Dec 27. pii: S0003-4967(25)04594-7. [Epub ahead of print]

Identification of novel fibroblast subsets in diffuse cutaneous systemic sclerosis.

Ann-Helen S Rosendahl, Anna Bornikoel, Isabel Zeinert, Lena Keufgens, Frederik Tellkamp, Niklas Kleinenkuhnen, Till Baar, Katrin Schönborn, Marcus Krüger, Achim Tresch, Bent Brachvogel, Beate Eckes, Pia Moinzadeh, Thomas Krieg.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune-driven fibrotic disease, characterised by excessive extracellular matrix (ECM) deposition and fibroblast activation. Our study aimed to identify novel fibroblast subpopulations in SSc and determine their functional role.
METHODS: We performed single-cell RNA sequencing on cultured dermal fibroblasts from healthy donors and patients with diffuse cutaneous SSc, verified selected, specific genes at the protein level and used siRNA knockdown experiments to provide evidence for a functional role of these proteins.
RESULTS: SSc fibroblasts revealed high heterogeneity and in specific activated subsets strong upregulation of CD9 and four and a half LIM domain 1 (FHL1), previously described as a muscle-related protein. Overexpression of FHL1 and CD9 was also detected in fibroblast subsets in patient skin. CD9 was associated with the regulation of FHL1 expression. Downmodulation of FHL1 in primary skin fibroblasts correlated with downregulation of the vestigial-like family member 3 (VGLL3) gene, which is known to be expressed in myofibroblasts in a stiff and fibrotic environment and to upregulate collagen synthesis. Further, VGLL3 was confirmed to be upregulated in SSc donor skin.
CONCLUSIONS: Our study identified novel fibroblast subsets in SSc, characterised by CD9 and/or FHL1 upregulation. The data indicate a functional role of FHL1 in fibroblasts and its involvement in the regulation of ECM production and provide a new mechanistic link to VGLL3 regulation. Our findings suggest new avenues for therapeutic exploration targeting the perpetuating fibroblast activation by the fibrotic environment.

DOI: https://doi.org/10.1016/j.ard.2025.11.027
Pancreatology. 2025 Dec 23. pii: S1424-3903(25)00727-6. [Epub ahead of print]

ORM2 alleviates pancreatic fibrosis in chronic pancreatitis by modulating autophagy via ZG16.

Bangwei Huang, Jianguo Gao, Yue Wang, Xin Tan, Ying Zhang, Zijian Si, Xinyi Yang, Xia Liu, Zhaoshen Li, Lianghao Hu, Pengyuan Wang.

   BACKGROUND: Chronic pancreatitis (CP) is a progressive fibro-inflammatory disorder with no effective anti-fibrotic treatment. Pancreatic stellate cells (PSCs) play a central role in pancreatic fibrosis by secreting excessive extracellular matrix (ECM) upon activation. Autophagy has been shown to promote PSC activation, yet its regulation remains unclear. This study focuses on ORM2, an acute-phase protein, and investigates whether it attenuates pancreatic fibrosis by modulating autophagy in PSCs.
METHODS: A CP mouse model was induced by repeated caerulein injections. Pancreas-specific ORM2 knockout and overexpression were achieved via AAV-mediated strategies. Human PSCs (HPSCs) and primary mouse PSCs were treated with TGF-β1 to induce fibrotic activation in vitro. Autophagic flux was assessed using Western blot, transmission electron microscopy, and LC3B-RFP-GFP reporter assays. Protein-protein interactions were identified using the SPIDER technique and co-IP assay.
RESULTS: ORM2 was significantly downregulated in pancreatic tissue but upregulated in serum and liver during CP. Pancreas-specific ORM2 knockout exacerbated pancreatic fibrosis, while ORM2 overexpression attenuated fibrotic markers (α-SMA, COL1A1, FN) and tissue collagen deposition. ORM2 suppressed TGF-β1-induced fibrotic gene expression and inhibited autophagic flux by blocking autolysosome formation in vitro. SPIDER and co-IP analysis identified ZG16 as an ORM2-binding protein. ZG16 knockout abolished the anti-fibrotic effects of ORM2 in vitro and in vivo.
CONCLUSION: ORM2 alleviates pancreatic fibrosis in CP by binding to ZG16 and inhibiting autophagy-driven PSC activation. These findings identify ORM2 as a promising therapeutic agent for pancreatic fibrosis.

Keywords:  Autophagy; Chronic pancreatitis; ORM2; Pancreatic fibrosis; ZG16

DOI:  https://doi.org/10.1016/j.pan.2025.12.019
Med Oncol. 2026 Jan 03. 43(2): 108

Single-cell profiling reveals lineage-specific fibroblast stromal subtypes drive ECM remodeling and immune modulation in the hepatocellular carcinoma tumor microenvironment.

Zhichao Jiang, Haitao Wang, Han Li, Zhiqiang Chen, Baiyu Sun.

  HCC is characterized by extensive ECM remodeling, primarily mediated by stromal cells. While cancer-associated fibroblasts are known contributors to tumor fibrosis, their transcriptional diversity and role in immune modulation within the HCC tumor microenvironment remain poorly resolved. Integrative analysis of six public HCC scRNA-seq datasets was employed to identify ECM-active stromal cells. High-ECM cells were re-clustered and fibroblast subtypes were defined through differential expression, pathway enrichment, lineage scoring and cell-cell interaction modeling. Spatial transcriptomic mapping and tissue-level profiling were performed to validate and prioritize ECM-related genes for experimental analysis. COL1A1 and COL3A1 were selected for siRNA-mediated knockdown in HepG2 and HepB3 cells followed by RT-qPCR, Western blot, proliferation, colony formation and wound healing assays. ECM activity analysis identified fibroblasts as the most ECM-enriched stromal population. Reclustering of ECM-high stromal cells identified eight distinct subtypes and targeted fibroblast clustering revealed five functionally diverse states. GO and spatial transcriptomic analysis confirmed subtype-specific functions and localization. In silico tissue profiling further prioritized COL1A1 and COL3A1 as pan-mesenchymal ECM genes enriched in fibrogenic fibroblast subsets. CellChat analysis revealed myofibroblasts and inflammatory CAFs as dominant signal senders. Knockdown reduced COL1A1 and COL3A1 expression at both mRNA and protein levels, and enhanced HCC cell proliferation, migration and colony formation. This study identifies transcriptionally and functionally distinct fibroblast subtypes in HCC and highlights COL1A1 and COL3A1 as key matrix-regulatory genes expressed in fibrogenic stromal subsets.

Keywords:  Extracellular matrix; Fibroblast heterogeneity; Hepatocellular carcinoma; Single-cell transcriptomics; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-025-03220-3
Mol Cells. 2025 Dec 29. pii: S1016-8478(25)00133-5. [Epub ahead of print] 100309

Roles of Exosome-derived Non-coding RNA in Fibrosis.

Yujing Wang, Zhixiang Le, Rujie Shi, Kun Li.

  Fibrosis is a chronic, progressive disease characterized by the excessive accumulation of extracellular matrix (ECM) in tissues and organs during damage-repair responses. This pathological process can involve almost any tissue or organ and may eventually lead to organ failure, posing a major threat to human health. ECM production is closely related to intercellular communication. As one of the biologically active substances participating in intercellular communication, exosomes have attracted increasing attention in recent years. In particular, non-coding RNAs (ncRNAs) enriched in exosomes regulate gene expression at multiple levels and influence the fibrosis process. Common ncRNAs include miRNA, lncRNA, circRNA and tRNA, which can be selectively loaded into exosomes by various cells to modulate receptor cell functions. In fibrosis-related diseases, the primary sources of exosome-derived ncRNAs (Exo-ncRNAs) include mesenchymal stem cells, macrophages, epithelial cells and fibroblasts. These Exo-ncRNAs regulate macrophage polarization, epithelial-mesenchymal transition, and fibroblast-myofibroblast transdifferentiation within the microenvironment. In this review, we summarize the regulatory roles and molecular mechanisms of these ncRNAs in the fibrosis process, and discusse Exo-ncRNAs with potential therapeutic effects. Understanding Exo-ncRNAs from different cells sources may provide new research directions for pathological intervention and the treatment of multi-organ fibrosis.

Keywords:  Exosome; Extracellular matrix; Fibrosis; Non-coding RNA

DOI:  https://doi.org/10.1016/j.mocell.2025.100309
Int J Mol Sci. 2025 Dec 13. pii: 12014. [Epub ahead of print]26(24):

Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential.

Patrizia Sabatell, Alberto Di Martino, Cesare Faldini, Paolo Bonaldo, Luciano Merlini, Vittoria Cenni.

  Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions.

Keywords:  CMD; COL6-related myopathies; Ullrich congenital muscular dystrophy; collagen VI; focal adhesion; joint contractures; mechanotransduction; primary cilium; tendon dysfunction; tendon extracellular matrix

DOI:  https://doi.org/10.3390/ijms262412014
Front Oncol. 2025 ;15 1730887

HMCN1 as a conserved biomarker of epithelial-mesenchymal transition: a cross-cancer analysis.

Yuanxi Leng, Yayun Liu, Le Zhi.

   Background: The extracellular matrix (ECM) critically regulates tumor progression, but the systematic role of its large constituent hemicentin-1 (HMCN1) across cancers remains poorly defined. Although implicated in cell invasion and migration, a comprehensive pan-cancer understanding of HMCN1 is lacking.
Methods: We performed an integrative multi-omics analysis of HMCN1 across 33 cancer types using data from TCGA, GTEx, and CPTAC. Based on prominent functional importance in bone tumors, osteosarcoma was selected for functional validation. In vitro experiments, including knockdown and overexpression, were conducted to assess effects on migration and invasion.
Results: HMCN1 was frequently upregulated in tumors and associated with poor prognosis. Its mutations correlated with genomic instability. HMCN1-high tumors were enriched in inflammatory immune subtypes and exhibited a dysfunctional tumor microenvironment. Pathway analysis consistently linked HMCN1 expression to epithelial-mesenchymal transition (EMT). Functional validation in osteosarcoma confirmed that HMCN1 knockdown suppressed, while its overexpression enhanced, cell migration and invasion through regulation of key EMT markers.
Conclusions: This study identifies HMCN1 as a novel, conserved regulator of EMT and a candidate prognostic biomarker across cancers. The findings in osteosarcoma provide a foundational rationale for developing HMCN1 as a potential therapeutic target.

Keywords:  EMT; biomarkers; hemicentin-1; osteosarcoma; pan-cancer

DOI:  https://doi.org/10.3389/fonc.2025.1730887
Comp Biochem Physiol Part D Genomics Proteomics. 2025 Dec 29. pii: S1744-117X(25)00326-0. [Epub ahead of print]58 101737

Transcriptional responses to DHA-induced lipid droplet accumulation in primary adherent mantle cells of Sinonovacula constricta (Lamarck, 1818).

Bowen Yan, Zhaoshou Ran, Qiang Zhou, Jiaxin Zhu, Fei Kong, Jilin Xu.

  Docosahexaenoic acid (DHA), an essential omega-3 long-chain polyunsaturated fatty acid, is crucial for the development of marine mollusks. Despite its importance, the molecular mechanisms of DHA action in these organisms are poorly understood, primarily due to the lack of reliable in vitro models. This study utilizes the razor clam Sinonovacula constricta as a model organism, establishing a primary adherent cell culture from various tissues, with mantle tissue identified as the optimal source for its rapid migration and low contamination risk. Cells incubated with varying concentrations of DHA (0-400 μM) for 6 h exhibited a concentration-dependent accumulation of lipid droplets (LDs), highlighting the model's suitability for investigating lipid metabolism. Transcriptomic analysis of cells treated with 50 μM DHA identified 848 differentially expressed genes (DEGs), with 747 upregulated and 101 downregulated, indicating the complex effects of DHA. The top 20 significantly upregulated and downregulated DEGs revealed significant involvement in cell signaling transduction, extracellular matrix organization, and substance transport and metabolism. Particularly, lipid metabolism genes, including perilipin 2 and abhydrolase domain containing 2, as well as pathways such as the PPAR signaling pathway and sphingolipid metabolism, were significantly altered, suggesting a reprograming of fatty acid metabolism contributing to LD accumulation. Additionally, pathways related to immune response were notably affected, potentially enhancing cellular health. Collectively, this study provides the first comprehensive insights into the molecular mechanisms underlying DHA-induced LD accumulation in a marine mollusk model at the cellular level, laying a foundation for developing precise nutritional strategies involving DHA in S. constricta aquaculture.

Keywords:  DHA; Fatty acids; Lipid droplet; Marine mollusks; Transcriptome

DOI:  https://doi.org/10.1016/j.cbd.2025.101737
Bioorg Chem. 2025 Dec 25. pii: S0045-2068(25)01295-7. [Epub ahead of print]169 109415

Synthesis and radiolabelling strategies of fibroblast activation protein ligands: a review.

Anna Tolomeo, Lorenza Marinaccio, Eleonora Procino, Sara D'Ingiullo, Azzurra Stefanucci, Vincenzo Dimiccoli.

  Fibroblast activation protein (FAP) has been the subject of several studies as a promising molecular target for cancer diagnostics and therapy. Fibroblast activation protein (FAP) is overexpressed on the surface of cancer-associated fibroblasts (CAFs). The latter represent a key element of the tumour microenvironment (TME) thanks to their ability to remodel the extracellular matrix, promote angiogenesis and suppress antitumor immune responses. Based on this rationale, many FAP inhibitors have been developed, used as radiolabelled molecular imaging probes in nuclear medicine. Some of these investigational radiopharmaceuticals have already been extensively studied in clinical settings for cancer imaging, whereas other molecular imaging techniques, such as PET with [18F]FDG, have limitations, especially in tumours with low metabolic activity. In addition, FAPI derivatives have potential for theragnostic in delivering targeted cancer therapies. This systematic review provides an overview of the latest updates reported in literature on the synthesis and radiolabelling methods of FAP ligands, specifically on FAPI-04, FAPI-46, FAPI-74 and Onco-Fap. The main aim is to summarize the current methodologies, highlighting the key advancements and challenges in the development of these radiopharmaceuticals.

Keywords:  Cancer associated fibroblasts; Fibroblast activation protein; Molecular imaging; Radiopharmaceuticals; Theranostics; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.bioorg.2025.109415
Front Genet. 2025 ;16 1690319

A transcriptomic atlas at bulk and single-cell levels identifies novel transcriptional and splicing regulators of ECM homeostasis in osteoarthritis.

Xiguang Ye, Chunyan Zheng, Hao Li.

  Osteoarthritis (OA) is a common chronic degenerative joint disease. Chondrocytes undergo dynamic changes during the pathogenesis of OA, and the destruction of the extracellular matrix (ECM) and its homeostatic disruption are hallmarks of OA. This study explores the roles of transcriptional and alternative splicing (AS) mechanisms in regulating extracellular matrix (ECM) homeostasis in osteoarthritis (OA), using bulk and single-cell RNA-sequencing data. By analyzing two OA transcriptome datasets, we identified differentially expressed genes (DEGs) that are enriched in ECM-related pathways and constructed a regulatory network between differentially expressed transcription factors (DE TFs) and ECM-related DEGs. This revealed the potential roles of transcription factors ELF3 and DDIT3 in regulating the expression of COL3A1, COL5A2, and S100A4. Single-cell RNA-sequencing data further validated the expression patterns of ELF3 and DDIT3 in distinct chondrocyte subtypes. Additionally, by analyzing AS events, we identified the RNA-binding protein (RBP) KHDRBS3 as a regulator of AS for the ECM-related gene IL16. Aberrant changes in these events may impact the ECM environment of chondrocytes and contribute to the pathogenesis of OA. This study, for the first time, dissects the regulatory models in OA cartilage at both transcriptional and post-transcriptional levels. These findings provide novel potential targets for early diagnosis and intervention strategies in OA.

Keywords:  RNA-binding protein; alternative splicing; extracellular matrix; osteoarthritis; transcription factor

DOI:  https://doi.org/10.3389/fgene.2025.1690319
Int J Mol Med. 2026 Feb;pii: 50. [Epub ahead of print]57(2):

Astragaloside IV: A multipotent phytochemical for treating fibrotic diseases (Review).

Mingyu Wu, Ke Li, Jiabin Wu, Qiuyu Zhang, Xiaotong Ma, Wei Dai, Haoyang Gao, Xianyi Ding, Wenhong Wang, Weihua Xiao.

  Fibrosis is a maladaptive response of tissues or organs to adverse stresses, such as chronic inflammation, infection and mechanical injury. It further promotes parenchymal cell loss, abnormal myofibroblast proliferation and excessive extracellular matrix buildup, eventually triggering scar tissue hyperplasia or organ injury. Although a moderate fibrotic response is beneficial for compensatory tissue repair induced by exogenous or endogenous injury, excessive fibrosis is the basis for the promotion of multiorgan pathologies, such as cardiac hypertrophy, idiopathic pulmonary fibrosis, or renal tubulointerstitial fibrosis. In industrialized countries alone, fibrotic diseases account for ~45% of all‑cause mortality. Consequently, the development of medications that regulate the activation of growth factors, proliferation of fibrotic effector cells and deposition and degradation of the extracellular matrix is essential. Botanical compounds derived from Chinese medicine are generally considered natural tonics. Among these compounds, astragaloside IV (AS‑IV) is a bioactive product isolated from the roots of Astragalus membranaceus Bunge. On the basis of the multitarget therapeutic mechanism of Chinese herbal medicine, AS‑IV may have considerable benefits in improving multiorgan fibrosis and complex fibrotic diseases with multisignal cascades. It can effectively alleviate the fibrosis‑induced dysfunction of major tissues or organs, including the heart, lungs, kidneys and liver, by regulating the signal transduction of reactive oxygen species/caspase‑1/gasdermin D, transforming growth factor‑β/Smads, Wnt/β‑catenin and sirtuin 1‑nuclear factor‑κ B. The present review mainly focused on phytomedicine and highlights the potential of AS‑IV as an antifibrotic medication. It aimed to provide a novel reference for the application of AS‑IV in the nutritional intervention of fibrotic diseases.

Keywords:  astragaloside IV; fibrotic disease; mechanism; signaling pathway; target

DOI:  https://doi.org/10.3892/ijmm.2025.5721
Biochem Biophys Rep. 2026 Mar;45 102403

Signalling pathways in hepatocellular carcinoma (HCC) metastasis and invasion: Molecular mechanisms and therapeutic implications.

Jayanta Das, Bhupen Barman, Phulen Sarma, Bipul Kumar Das, Rajiv Chetia, Partha Pratim Kalita.

  HCC is one of the deadliest malignancies with a rising global occurrence and poor prognosis. Metastasis and invasion are essential processes in the HCC progression, and have a profound bearing on clinical outcome. This review explores the key signalling pathways involved in HCC metastasis and invasion, focusing on their molecular mechanisms, crosstalk, and therapeutic implications. Alongside the discussion of the Wnt/β-catenin, TGF-β, PI3K/AKT/mTOR, MAPK/ERK, HGF/c-MET, Notch and Hippo-YAP/TAZ pathways, are known to contribute to promoting aggressive HCC behaviour. Stromal interactions, extracellular matrix remodelling, hypoxia and angiogenesis as well as the tumour microenvironment are also highlighted. These pathways are subject to current therapeutic treatments in the form of tyrosine kinase inhibitors and monoclonal antibodies, and research prospective of the Wnt/β-catenin blocker, TGF-β inhibitors, etc. The variations in tumours and resistance patterns to treatment and their existing problems in treating HCC are addressed. The review evaluates new therapeutic targets offering a foundation for further research and clinical advancements in this challenging field.

Keywords:  Hepatocellular carcinoma; Invasion; Metastasis; Signalling pathways; Targeted therapy; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.bbrep.2025.102403
Int J Mol Sci. 2025 Dec 11. pii: 11950. [Epub ahead of print]26(24):

Regulation of Tissue Regeneration by Immune Microenvironment-Fibroblast Interactions.

Boram Son.

  Tissue regeneration is a highly complex and dynamic process critically influenced by the immune microenvironment and its multifaceted interactions with fibroblasts. Traditionally regarded as structural cells responsible for extracellular matrix (ECM) production, fibroblasts have recently emerged as active regulators orchestrating immune responses and tissue repair. This review focuses on the reciprocal crosstalk between fibroblasts and key immune components, including macrophages, T cells, ECM, local pH, and signaling proteins. These interactions coordinate the initiation and resolution phases of inflammation, regulating fibroblast migration, proliferation, differentiation, and ECM deposition, which collectively determine the efficiency and quality of tissue repair. Special attention is given to the dynamic modulation of the immune microenvironment that governs fibroblast behavior during injury and regeneration. Finally, recent therapeutic strategies targeting this crosstalk-from molecular inhibitors to cell-based therapies-are discussed, highlighting emerging avenues for enhancing regenerative outcomes and mitigating fibrotic diseases. This integrated perspective positions fibroblast-immune interactions as a promising frontier in regenerative medicine, offering new opportunities for targeted tissue repair and control of chronic inflammation.

Keywords:  cell signaling; extracellular matrix; fibroblast; immune microenvironment; inflammation; tissue regeneration

DOI:  https://doi.org/10.3390/ijms262411950
Cancer Cell Int. 2025 Dec 30.

TAGLN: a stiffness-driven prognostic biomarker for metastatic colorectal cancer.

Yanshuo Ye, Yiyang Jia, Wei Li.

  TAGLN is identified as a key prognostic gene in colorectal cancer through TCGA-COAD analysis, with high expression correlating with poor survival and advanced tumor stage. Functionally, TAGLN overexpression promotes epithelial-mesenchymal transition and enhances cancer cell migration. Transcriptomic profiling reveals its involvement in extracellular matrix remodeling and cell adhesion pathways. Mechanistically, TAGLN expression is upregulated by stiff tumor-mimicking extracellular matrix and is correlated with key mediators of collagen crosslinking and EMT. Clinically, TAGLN exhibits progressive overexpression from normal epithelium to primary tumors and metastatic lesions. These findings establish TAGLN as a stiffness-responsive regulator of ECM remodeling and EMT, driving colorectal cancer metastasis and serving as a potential therapeutic target.

Keywords:  Colorectal cancer; Epithelial-mesenchymal transition; Extracellular matrix; TAGLN

DOI:  https://doi.org/10.1186/s12935-025-04157-3
Acta Pharm Sin B. 2025 Dec;15(12): 6141-6162

Emerging epigenetic modifications in renal fibrosis: From mechanisms to treatments.

Xiaoguo Suo, Qinglin Ge, Lijin Peng, Qi Zhu, Mengmeng Zhang, Xinran Cheng, Fang Wang, Juan Jin, Jianan Wang, Xiaoming Meng.

  Chronic kidney disease (CKD) has emerged as a formidable global health challenge, with a marked increase in its incidence, prevalence, and mortality rates. Renal fibrosis is a central pathophysiological process that drives the progression of CKD to end-stage renal disease. Despite its crucial role in CKD progression, effective clinical interventions to delay or mitigate renal fibrosis remain limited. A deeper understanding of the molecular mechanisms underlying renal fibrosis, along with the identification of potential drug targets and the development of novel therapeutics, holds immense research significance and clinical value for the prevention and treatment of CKD. In recent years, epigenetic research has garnered widespread attention and plays a pivotal role in various disease processes. Against this backdrop, the mechanisms by which epigenetic modifications exert their effects on renal fibrosis are gradually being elucidated, offering novel insights into the understanding of CKD. In this review, we summarize and analyze the intricate regulatory network of epigenetic modifications in renal fibrosis. We explore the promising antifibrotic effects demonstrated by various epigenetically modified drugs in fibrotic kidney models and discuss the challenges and opportunities in current research. These findings provide crucial insights for a deeper understanding of the molecular mechanisms underlying renal fibrosis and the development of novel therapeutic approaches.

Keywords:  CKD; DNA modification; Disease treatment; Epigenetics; Histone modification; RNA modification; Renal fibrosis; Therapeutic targets

DOI:  https://doi.org/10.1016/j.apsb.2025.09.012
Tissue Cell. 2025 Dec 29. pii: S0040-8166(25)00583-X. [Epub ahead of print]99 103301

Fibrin hydrogel incorporated with microspheres containing vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) accelerated the healing of diabetic wounds in rats.

Abdullah Albelasi, Suad A Alghamdi, Mohammed Alissa.

  Diabetic wounds are characterized by delayed healing due to impaired angiogenesis, chronic inflammation, and defective extracellular matrix formation. This study evaluated the therapeutic potential of a fibrin hydrogel incorporating microspheres loaded with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (FHM) in promoting wound repair in a streptozotocin-induced diabetic rat model. Rats were randomly assigned to control, fibrin hydrogel alone (FH), or FHM groups, and wounds were assessed on days 7 and 14. Mechanical properties, stereological parameters, collagen deposition, and cytokine expression were analyzed. FHM treatment significantly improved tensile strength and stress-bearing capacity of the wound tissue compared to FH and control groups (P < 0.05). Stereological analysis revealed increased fibroblast proliferation and neovascularization, with a concomitant reduction in inflammatory cell infiltration in FHM-treated wounds at both time points (P < 0.05). Masson's trichrome staining demonstrated enhanced collagen deposition and maturation in the FHM group, indicating improved extracellular matrix remodeling. Molecular analysis showed elevated transforming growth factor beta (TGF-β) and VEGF expression, alongside decreased pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), suggesting a dual effect of promoting regeneration while attenuating inflammation. This multimodal approach holds promise as a potential therapeutic strategy for chronic diabetic wounds, offering both functional and structural benefits. Further long-term studies and clinical translation are warranted to evaluate safety and efficacy in human patients.

Keywords:  Angiogenesis; BFGF; Collagen deposition; Diabetic wound; Fibrin hydrogel; Fibroblast proliferation; Microspheres; VEGF

DOI:  https://doi.org/10.1016/j.tice.2025.103301
Adv Gerontol. 2025 ;38(4): 595-604

[The extracellular matrix of senescent stromal cells decreased secretion of SDF-1 and HGF by endothelium.]

D K Matveeva, D N Kashirina, A Y Ratushnyy.

The process of mesenchymal stromal cells (MSCs) senescence is accompanied by alterations in their extracellular matrix (ECM), which has the potential to compromise cellular interactions within the perivascular niche. In this study, the effect of the ECM of senescent MSCs obtained in a «stress-induced model» on the paracrine activity of endothelial cells (ECs) in vitro was investigated. Senescent MSCs exhibited reduced production of structural and adhesive ECM proteins (including type I collagens, fibulins, perlecan, et al.) and increased deposition of senescence-associated molecules (PAI-1, GDF-15). When ECs were cultured on decellularized ECM of senescent MSCs, a significant decrease in the secretion of angiogenic and chemoattractant factors (SDF-1, HGF) was observed compared to young ECM. These findings highlight a potential role of ECM-mediated mechanisms in the development of age-related vascular pathologies and may provide a foundation for the design of anti-senescent therapeutic strategies.

Keywords: cellular senescence; endothelium; extracellular matrix; mesenchymal stromal cells
Front Oncol. 2025 ;15 1687984

LncRNA ZFHX4-AS1 initiates an oncogenic axis involving a ZFHX4/SOX2 positive feedback loop to accelerate glioma progression.

Hongshan Yan, Xue Wang, Zongmao Zhao.

   Introduction: The long non-coding RNA ZFHX4-AS1 is a recently identified transcript with an unknown role in glioma. Here, we demonstrate that ZFHX4-AS1 and its neighboring protein-coding gene, ZFHX4, are both significantly upregulated in glioma, and their high expression correlates with poor patient prognosis.
Methods: We integrated pan-cancer and glioma transcriptomic datasets from TCGA to assess ZFHX4-AS1 and ZFHX4 expression patterns and their prognostic relevance. We analyzed the expression of ZFHX4-AS1 and its neighboring gene ZFHX4 in human glioma tissues and correlated it with patient prognosis. Functional assays, including cell proliferation, migration, and invasion tests, were conducted in vitro, and tumor growth was assessed in vivo. Additional mechanistic assays-including RNA-FISH, subcellular fractionation, and co-immunoprecipitation-were performed to determine the localization and molecular interactions of ZFHX4-AS1. The mechanistic interactions between ZFHX4-AS1, ZFHX4, SOX2, and the JAK-STAT pathway were investigated using gene expression analysis, protein-protein interaction studies, and signaling pathway activation assays.
Results: Functionally, both ZFHX4-AS1 and ZFHX4 promote glioma cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, ZFHX4-AS1 acts in cis to positively regulate the expression of ZFHX4. Crucially, we identified the stemness factor SOX2 as a key functional partner of ZFHX4. ZFHX4 and SOX2 physically interact and form a positive feedback loop, where each protein promotes the other's expression. This regulatory circuit serves to amplify the oncogenic signal, robustly driving the malignant phenotype. Finally, we demonstrate that this signaling axis converges on the activation of the JAK-STAT pathway.
Discussion: In conclusion, our study significantly expands upon the understanding of the ZFHX4-AS1 pathway in glioma. We demonstrate that ZFHX4-AS1 initiates an oncogenic signal which is powerfully amplified by a previously unidentified ZFHX4/SOX2 positive feedback loop. We further establish that this entire axis ultimately converges on the activation of the JAK-STAT pathway. This detailed ZFHX4-AS1/ZFHX4/SOX2/JAK-STAT axis represents a promising set of therapeutic targets for glioma treatment.

Keywords:  SOX2; ZFHX4; ZFHX4-AS1; glioma; long non-coding RNA

DOI:  https://doi.org/10.3389/fonc.2025.1687984
Medicina (Kaunas). 2025 Nov 27. pii: 2112. [Epub ahead of print]61(12):

Proteoglycans in Prostate Cancer Progression and Therapy Resistance.

Ivana Samaržija.

  The extracellular matrix (ECM) is a complex noncellular network of (macro-)molecules that surrounds and supports diverse cells in tissues and organs. In cancer, ECM is a part of the tumor microenvironment (TME) that embeds its cellular components including cancer cells and the neighboring non-cancerous stromal cells such as fibroblasts, endothelial, and immune cells. Given the complexity of players and interactions that the ECM participates in and is exposed to in the TME, it does not come as a surprise that many of the processes that drive cancer progression take part precisely in the ECM compartment of the TME. Along with diverse glycoproteins and collagens, proteoglycans (PGs) are among the main components of the core ECM. PGs are composed of a protein core to which glycosaminoglycan chains are attached. Considering the structural diversity of these molecules and their 'hybrid' nature, it is not surprising that they are involved in a variety of processes that are vital for surrounding cells. Moreover, they are secreted by both cancer and stromal cells, contributing to the complexity of interactions in the TME. In prostate cancer, PGs have been shown to be involved in many steps of its progression; the most prominent examples include the seemingly tumor-promoting roles of versican, perlecan, and biglycan, and the tumor-suppressive roles of decorin and betaglycan. The role of syndecan 1 is a bit more complex; namely, the nature of its role is context dependent. In this narrative review article, the roles of PGs in prostate cancer progression and therapy resistance are discussed in more detail.

Keywords:  biomarker; cancer progression; extracellular matrix; prostate cancer; proteoglycan; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/medicina61122112
Mol Cell Biol. 2025 Dec 29. 1-25

Xiangpi Shengji Ointment Accelerates Anal Fistula Healing by Regulating Macrophage-Fibroblast Crosstalk Through the Nuclear Factor Kappa B/Hypoxia-Inducible Factor Alpha/Vascular Endothelial Growth Factor Signaling Axis.

Kui Li, Jiaqing Xiong, Sai Yang, Mintao Jian.

  This study elucidates the molecular mechanism by which Xiangpi Shengji ointment (Xiangpi Shengji gao, XPSJG) promotes anal fistula wound healing. Integrated network pharmacology and transcriptomic analyses (GSE28914, GSE203244) revealed the involvement of the NF-κB/HIF-α/VEGF axis, with elevated expression of NF-κB, HIF1A, and VEGFA observed during the early healing phase (days 3 and 7). Single-cell RNA sequencing further indicated that activation of this signaling axis may drive early macrophage M1 polarization. In vitro experiments confirmed early treatment with the aqueous extract of XPSJG powder significantly enhanced macrophage M1 polarization and upregulated VEGF, COL1A1, and α-SMA, promoting fibroblast proliferation and migration (assessed via CCK-8, ELISA, WB, RT-qPCR). In vivo, using a murine anal fistula model, XPSJG accelerated wound closure, improved tissue architecture, and reduced inflammation and apoptosis through modulation of the NF-κB/HIF-α/VEGF axis. These effects were partially reversed by an NF-κB inhibitor, further verifying pathway involvement. Collectively, the findings demonstrate that early application of XPSJG facilitates anal fistula healing by inducing macrophage M1 polarization and enhancing fibroblast function via the NF-κB/HIF-α/VEGF signaling axis, thereby providing a mechanistic rationale for its clinical use in chronic wound management.

Keywords:  NF-κB/HIF-α/VEGF pathway; Xiangpi Shengji ointment; anal fistula healing; fibroblast function; macrophage polarization

DOI:  https://doi.org/10.1080/10985549.2025.2597464