bims-fibdiv 2025-12-21 papers

bims-fibdiv

Biomed News

on Fibroblast diversity

Issue of 2025–12–21
fourteen papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary

Transient versican expression is required for β1-integrin accumulation during podocyte layer morphogenesis in amphibian developing kidney.
A transition zone enriched WIF1 ⁺ basal cell subtype is associated with benign prostatic hyperplasia.
The roles of Tenascin C in kidney diseases.
Fibroblast pentose phosphate pathway activation upon decreased circPLCE1 exacerbates intestinal fibrosis in Crohn's disease.
Fibroblast-Based Therapies for Wrinkles, Wounds, and Vitiligo: A Comprehensive Review.
Cellular mechanosensing on a cell-scale stiffness gradient substrate.
Toward the Origin and Evolution of Unique Echiurid Excretory Organs: New Data From Females of Bonellia viridis.
Berberine facilitates alveolar bone regeneration via Ptgs2-mediated dual regulation of osteoblast differentiation and fibroblast inhibition.
SLC44A4 modulates the extracellular matrix through the PI3K/AKT signaling pathway, thereby affecting the proliferation, migration, and invasion of ovarian clear cell carcinoma (OCCC).
Molecular drivers of osteogenesis imperfecta: a cellular and extracellular collagen disease.
Obtusifolin mitigates CCl4-induced inflammation and liver fibrosis by modulating the ROCK2/ Cofilin-1 / NFκB pathway.
Idiopathic Pulmonary Fibrosis: Cellular Heterogeneity, Mechanisms, and Therapeutic Implications.
Preclinical research of dihydromyricetin for fibrotic diseases.
MEGF8-driven metabolic reprogramming and immune evasion define a high-risk subtype of endometriosis-associated ovarian cancer.

Cells Dev. 2025 Dec 13. pii: S2667-2901(25)00069-5. [Epub ahead of print]185 204062

Transient versican expression is required for β1-integrin accumulation during podocyte layer morphogenesis in amphibian developing kidney.

Isabelle Buisson, Jean-François Riou, Muriel Umbhauer, Ronan Le Bouffant, Valérie Bello.

  The functional organization of the vertebrate nephron is remarkably conserved, yet the morphogenetic processes underlying nephrogenesis vary across species and kidney types. The Xenopus larval kidney, the pronephros, is a non-integrated nephron where plasma filtrates are first released into a coelomic compartment, the nephrocoel, before entering the tubular compartment through ciliated nephrostomes. Mechanisms of pronephros morphogenesis, especially the role of the extracellular matrix (ECM), remain poorly understood. This study investigates the function of the ECM component versican (vcan) in the development of the pronephric kidney in X. laevis, focusing on non-integrated nephron features: the glomus, nephrocoel, and nephrostomes. Vcan is dynamically expressed in the ECM surrounding the developing tubule and the podocyte layer of the glomus, with transient presence in the differentiating podocyte region prior to the formation of the concave podocyte pocket that accumulates β1-integrin. Morpholino-mediated vcan depletion leads to fusion of proximal tubule branches, tubular dilation, and loss of proximal convolutions, without affecting nephrostomes. Glomus morphogenesis is severely disrupted, the podocyte layer fails to form its characteristic C-shaped structure, and β1-integrin fails to accumulate, although the podocyte differentiation marker nphs2 remains expressed. Other ECM components, including fibrillin, laminin, and fibronectin, remain correctly localized, indicating that the phenotype is not due to general ECM disorganization. Together, these findings identify a specific and temporally regulated role for vcan in glomus morphogenesis, likely by enabling β1-integrin accumulation and promoting cell-ECM interactions essential for proper podocyte layer assembly, thereby refining our understanding of ECM dynamics in kidney development.

Keywords:  Extracellular matrix (ECM); Glomus; Podocyte; Pronephros; Versican (vcan); X. laevis; β1-integrin

DOI:  https://doi.org/10.1016/j.cdev.2025.204062
bioRxiv. 2025 Dec 11. pii: 2025.12.08.692826. [Epub ahead of print]

A transition zone enriched WIF1 ⁺ basal cell subtype is associated with benign prostatic hyperplasia.

Rulin Wang, Qizhi Zheng, Mindy K Graham, Ajay Vaghasia, Jianyong Liu, Jordan Gregg, Tracy Jones, Anuj Gupta, Nicole Castagna, Yan Zhang, Kornel Schuebel, Jennifer Meyers, Alyza Skaist, Dixie Hoyle, Yuhan Yang, William G Nelson, Angelo M De Marzo, Srinivasan Yegnasubramanian.

The cellular composition and disease susceptibilities of the distinct zones of the human prostate remain incompletely understood. Through extensive single-cell RNA sequencing (scRNA-seq) of benign regions from prostatectomy specimens, we identified a basal cell population expressing WIF1, VCAN , and NRG1 , among other genes, that was significantly enriched in the transition zone (TZ). Benign prostatic hyperplasia (BPH) is a common condition that causes widespread morbidity and is nearly exclusively localized to the TZ. Analysis of previously published scRNA-seq datasets further confirmed that WIF1 + basal cells were significantly enriched in BPH compared to normal prostate. Pathway and cell-cell communication analyses revealed that this basal subtype is associated with programs related to cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, and hormone response. Together, the molecular signature, zonal distribution, and pathway enrichment suggest that TZ-enriched WIF1 + basal cells may contribute to BPH pathogenesis by promoting epithelial and stromal remodeling.

DOI: https://doi.org/10.64898/2025.12.08.692826
Am J Physiol Cell Physiol. 2025 Dec 19.

The roles of Tenascin C in kidney diseases.

Tim Caspers, Peter Boor, Barbara Mara Klinkhammer.

  Tenascin C (TNC), an extracellular matrix glycoprotein, is crucial for embryonic development and tissue repair, inflammation, extracellular matrix remodelling, and fibrosis, particularly in kidney diseases. While its expression is typically low in healthy adult kidneys, TNC is upregulated in various kidney disease conditions including acute kidney injury (AKI) and chronic kidney disease (CKD). TNC influences fibroblast activation and elevated TNC levels correlate with CKD severity, highlighting its potential as a biomarker for diagnosis and monitoring of fibrogenesis. TNC's multifaceted role offers opportunities for therapeutic interventions. Here we provide an overview of TNC's structural and functional attributes, its regulatory mechanisms, and its multifactorial role in kidney disease development and progression. We also discuss recent approaches aiming to use TNC as a target for diagnostic and therapeutic purposes.

Keywords:  TNC; biomarker; extracellular matrix; fibroblast activation; fibrosis

DOI:  https://doi.org/10.1152/ajpcell.00514.2025
Gut. 2025 Dec 13. pii: gutjnl-2025-336415. [Epub ahead of print]

Fibroblast pentose phosphate pathway activation upon decreased circPLCE1 exacerbates intestinal fibrosis in Crohn's disease.

Longyuan Zhou, Jing Nie, Zhiyin Feng, Rongchang Li, Pingxin Zhang, Sinan Lin, Yao Zhang, Florian Rieder, Changhao Chen, Minhu Chen, Ren Mao.

   BACKGROUND: Intestinal fibrosis, a hallmark complication of Crohn's disease (CD), frequently progresses to stricture formation and surgical intervention. Fibroblast metabolic reprogramming is important in organ fibrosis. However, its role in intestinal fibrogenesis of CD remains elusive.
OBJECTIVE: We aim to explore the metabolic reprogramming of fibroblasts and its upstream regulators during intestinal fibrosis of CD.
DESIGN: We performed metabolome, single-cell RNA sequencing and spatial transcriptome on paired mucosal and submucosal tissue from the strictured and adjacent non-strictured intestinal segments. The candidate metabolite and metabolic enzymes were verified in primary human intestinal myofibroblasts (HIMFs) and dextran sulfate sodium-induced intestinal fibrotic mice. Next, we identified fibrosis-associated circPLCE1 to regulate the pentose phosphate pathway (PPP) using the circRNA transcriptome. Finally, we studied the functions and mechanisms of circPLCE1 using metabolome, transcriptome, metabolic flux, seahorse assay and RNA pull-down assay in HIMFs and fibroblast-specific circPLCE1 knockdown mice.
RESULTS: Multilayer integrated analysis identified activation of PPP in fibroblasts during intestinal fibrosis of CD. Specifically, xylulokinase (XYLB)-generated xylulose-5-phosphate (Xu5P) promoted extracellular matrix synthesis by epigenetic upregulation of collagen transcription. Moreover, downregulation of circPLCE1 in fibroblasts activated PPP, resulting in increased glycolysis, nicotinamide adenine dinucleotide phosphate production and aggravated intestinal fibrosis in vitro and in vivo. Mechanistically, circPLCE1 directly bound the domain-I of XYLB and competitively inhibited its enzymatic activity. Decreased circPLCE1 restored XYLB activity and accumulation of Xu5P in intestinal fibrosis.
CONCLUSION: Our findings delineate a circPLCE1/XYLB/Xu5P axis in fibroblasts which orchestrates PPP and fibrogenesis, unveiling a novel therapeutic target for intestinal fibrosis of CD.

Keywords:  CROHN'S DISEASE

DOI:  https://doi.org/10.1136/gutjnl-2025-336415
Dermatol Surg. 2025 Sep;51(9S): S12-S17

Fibroblast-Based Therapies for Wrinkles, Wounds, and Vitiligo: A Comprehensive Review.

Claire M Noell, Robert A Weiss.

BACKGROUND: Fibroblasts are essential dermal cells that produce extracellular matrix and growth factors critical for skin integrity, repair, and pigmentation. Their therapeutic use has expanded into clinical dermatology for various indications.
OBJECTIVE: To review and synthesize clinical evidence on autologous and allogeneic fibroblast therapies in the treatment of wrinkles, wounds, and vitiligo, highlighting mechanisms of action, safety profiles, and future applications.
METHODS: A comprehensive literature review was conducted of clinical trials involving fibroblast-based therapies in human subjects for skin aging, nonhealing wounds, and vitiligo. Data from randomized controlled trials and observational studies were extracted.
RESULTS: Autologous fibroblast injections (e.g., autologous fibroblast product-T) have demonstrated improvement in facial wrinkles with durable results and minimal adverse effects. Allogeneic fibroblast-based skin substitutes (e.g., Dermagraft, Apligraf) have shown efficacy in chronic wound healing, particularly in diabetic and venous ulcers. Emerging data suggest that fibroblasts may play a supportive role in vitiligo repigmentation. Both autologous and allogeneic fibroblasts have shown favorable safety profiles.
CONCLUSION: Fibroblast-based therapies offer a regenerative approach to a range of dermatologic conditions. Clinical evidence supports their use in wrinkle reduction and wound healing, with early promise in vitiligo. Fibroblast therapy exemplifies a shift toward biologically integrative treatments in dermatologic surgery.

DOI: https://doi.org/10.1097/DSS.0000000000004799
Soft Matter. 2025 Dec 17.

Cellular mechanosensing on a cell-scale stiffness gradient substrate.

Indrajit Bhattacharjee, Gautam V Soni, Bibhu Ranjan Sarangi.

Cells have the ability to sense and respond to various mechanical cues from their immediate surroundings. One of the manifestations of such a process, which is also known as "mechanosensing", is directed cell migration. Various biological processes have been shown to be controlled by extracellular matrix (ECM) stiffness. Substrates with a high stiffness gradient have been used as a platform to investigate cellular motion in response to mechanical cues. However, creating a cell scale stiffness gradient in such a cell adhesion friendly substrate still remains elusive. In this study, we present a simple and versatile method for fabricating substrates with a periodically varying stiffness profile at the cellular scale, featuring customizable high stiffness gradients. Fibroblast cells, when presented with such continuous yet anisotropic variation of stiffness, preferentially position their nuclei in stiffer regions of the substrate and align themselves along the direction of the lowest rigidity gradient. Furthermore, when the rigidity of the substrate is sufficiently high, cells exhibit less sensitivity to stiffness gradients, with their elongation and nuclear positioning becoming independent of stiffness variations. Overall, our experimental results reveal new insights into the process of cellular mechanosensing where the cell-scale gradient drives strong positional and orientational order.

DOI: https://doi.org/10.1039/d5sm00592b
J Morphol. 2025 Dec;286(12): e70105

Toward the Origin and Evolution of Unique Echiurid Excretory Organs: New Data From Females of Bonellia viridis.

Peter Kuznetsov, Elena Temereva.

Echiurids, as nonsegmented annelids, have an excretory system of a special organization. The excretory system of the echiuran worms is known to consist of ultrafiltration zones on blood vessels and anal sacs. Prior to this study, the fine structure of the anal sacs had been described in detail only for Thalassema thalassemum (Thalassematinae). In contrast, the more complex anal sacs of Bonelliinae, which contain additional structural elements such as tubules, remained unexplored. This study describes the anatomy, histology, and ultrastructure of the anal sacs of Bonellia viridis Rolando, 1822 (Bonelliinae) using a set of modern morphological methods: computer microtomography, araldite histology, scanning and transmission electron microscopy. New data suggest functional implications for structural elements of the anal sacs: the conical part and the neck of the funnel, the tubules, and the end sac. The ciliary funnels are responsible for collecting filtrate to their conical parts and can close at their base, thus preventing reverse flow. According to the ultrastructural data, the inner epithelium of the tubules and the end sac modifies the incoming filtrate in two ways. The inner epithelium of the tubules carries out pinocytosis and accumulates electron-dense granules. The inner epithelium of the end sac has a basal labyrinth consisting of basal processes with numerous mitochondria extending deep into the extracellular matrix and indicates active ion transport. Additional zones responsible for ultrafiltration were identified in the outer epithelium of the anal sac-specifically within the tubule and at the base of the funnel. The origin of the echiurid anal sacs as a result of fusion and multiplication of the metanephridia at the posterior growth zone of metameric annelid-like ancestor is suggested.

DOI: https://doi.org/10.1002/jmor.70105
Phytomedicine. 2025 Dec 07. pii: S0944-7113(25)01313-3. [Epub ahead of print]150 157678

Berberine facilitates alveolar bone regeneration via Ptgs2-mediated dual regulation of osteoblast differentiation and fibroblast inhibition.

Tian Li, Shanfeng Lin, Hongjuan Cao, Dalai Hasi, Xiaohan Liu, Lin Wu.

   BACKGROUND: Guided bone regeneration (GBR) is widely used for localized bone augmentation in the oral-maxillofacial region, but traditional GBR membranes are limited by their biofunctionality and mechanical properties. Berberine (BBR) has been reported to inhibit fibrosis and promote bone regeneration, yet it remains unclear whether BBR can simultaneously suppress fibroblast activity while enhancing osteogenic differentiation.
PURPOSE: This study aims to identify the optimal BBR concentration and its dual mechanisms in inhibiting fibroblast proliferation while promoting osteogenic differentiation, potentially providing an alternative to the barrier function of traditional GBR membranes.
METHODS: The optimal BBR concentration and its effects on fibroblast proliferation and osteogenic differentiation were evaluated in vitro. Network pharmacology and proteomics were used to investigate the potential mechanisms. A rat model of alveolar bone defects was used to evaluate the reparative effect of BBR. Seahorse analysis, electron microscopy, and immunofluorescence were employed to explore BBR's regulatory effect on mitochondrial function in both cell types.
RESULTS: BBR at 10 and 15 μM optimally promotes osteoblast dominance within the wound healing microenvironment, induces G1-phase arrest in fibroblasts, and promotes osteogenic differentiation. Mechanistically, BBR directly binds to prostaglandin-endoperoxide synthase 2 (Ptgs2) and upregulates Ptgs2 to achieve the dual effects. In vivo, the bone regeneration effect of the BBR and Bio-Oss® (a commercial bone substitute) combination was similar to that of the Bio-Oss® and Bio-Gide® combination (a commercial collagen membrane). Furthermore, distinct COX-2 localization patterns were observed following BBR treatment, with enhanced mitochondrial localization in osteoblasts and nuclear localization in fibroblasts, coupled with altered mitochondrial energy metabolism.
CONCLUSIONS: Our study suggests that optimal concentrations of BBR can inhibit fibroblast proliferation and promote osteogenic differentiation, thereby enhancing bone regeneration. Combined with spatial maintenance materials, BBR presents a promising alternative to traditional GBR membranes for improving clinical outcomes in oral bone augmentation and defect repair.

Keywords:  Berberine; Fibroblasts; Guided bone regeneration; Mitochondria; Osteoblasts; Ptgs2

DOI:  https://doi.org/10.1016/j.phymed.2025.157678
Cytotechnology. 2026 Feb;78(1): 17

SLC44A4 modulates the extracellular matrix through the PI3K/AKT signaling pathway, thereby affecting the proliferation, migration, and invasion of ovarian clear cell carcinoma (OCCC).

Tian Li, Wenyu Song, Suli Liu, Huafan Chang, Xiaojie Wang, Qin Yao, Kejuan Song.

  SLC44A4 is involved in the transmembrane transport of choline and other organic cations, influencing phospholipid metabolism in cell membranes and potentially participating in immune regulation. Ovarian clear cell carcinoma (OCCC), often diagnosed at advanced stages, exhibits poor responsiveness to conventional surgery and chemotherapy. Therefore, there is an urgent need to identify new biomarkers that can provide insights into the mechanisms underlying its onset and progression.To investigate the impact of SLC44A4 overexpression on the biological behavior of OCCC cells and to explore the underlying mechanisms.The effects of SLC44A4 on the proliferation, migration, and invasion of OCCC cells were assessed using CCK-8, colony formation, scratch, and Transwell assays. The impact of SLC44A4 on the extracellular matrix and PI3K/Akt signaling pathway was evaluated by Western blotting.SLC44A4 inhibited the proliferation and migration of OCCC cells in vitro, altered the extracellular matrix, and may inhibit the PI3K/Akt signaling pathway.SLC44A4 overexpression can alter the tumor microenvironment and inhibit the malignant progression of ovarian clear cell carcinoma (OCCC) by remodeling its extracellular matrix. These findings suggest that SLC44A4 may serve as a potential biomarker for evaluating the prognosis of OCCC.

Keywords:  Extracellular matrix; Ovarian clear cell carcinoma (OCCC); PI3K/Akt; SLC44A4; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10616-025-00881-w
Clin Sci (Lond). 2025 Dec 18. pii: CS20255642. [Epub ahead of print]139(24):

Molecular drivers of osteogenesis imperfecta: a cellular and extracellular collagen disease.

Silvia Cotti, Wendy Pérez Franco, Antonella Forlino.

  The clinical hallmarks of osteogenesis imperfecta (OI), often referred to as 'brittle-bone disease', are bone fragility and skeletal deformities that are usually accompanied by extra skeletal manifestations. OI is a family of collagen I-related disorders, currently classified into 23 distinct types and 5 OI-like forms, with variable phenotypic severity ranging from mild to lethal. At the molecular level, the pathophysiology of OI is driven by alterations in collagen I structure, primarily caused by dominant mutations in collagen genes (affecting approximately 85% of patients). It can also result from dominant, recessive, or X-linked defects in proteins involved in collagen biosynthesis, extracellular matrix organization, mineralization, or bone forming cell differentiation and/or activity. This review illustrates the different OI forms from a collagen I perspective, its complex biosynthetic process is first described, followed by a classification of the OI and OI-like causative mutations grouped based on whether the resulting collagen molecule is overmodified, undermodified, or unaltered. The underlying molecular mechanisms and the consequences at cellular and extracellular levels leading to the OI phenotype are discussed. An overview is provided on how newly discovered molecular pathways altered in OI can guide the development of innovative therapies aiming at increasing bone mass and improving bone quality in OI patients.

Keywords:  bone; collagen; heritable connective tissue disease; osteogenesis; osteogenesis imperfecta; post-translational modifications; rare bone disorders

DOI:  https://doi.org/10.1042/CS20255642
Eur J Pharmacol. 2025 Dec 16. pii: S0014-2999(25)01233-6. [Epub ahead of print] 178479

Obtusifolin mitigates CCl4-induced inflammation and liver fibrosis by modulating the ROCK2/ Cofilin-1 / NFκB pathway.

Suriya Panneerselvam, Nidhi Sharma, Sai Balaji Andugulapati.

  Liver fibrosis is a progressive clinical condition characterised by an abnormal accumulation of extracellular matrix (ECM) components, which are predominantly generated by activated hepatic stellate cells (HSCs) and other fibrogenic cells. This process leads to liver stiffness, which can progress to cirrhosis, an irreversible condition, and ultimately result in liver failure. Obtusifolin (OBT), an anthraquinone derivative isolated from the seeds of Senna obtusifolia, is known for its potent anti-inflammatory and antioxidant properties. The present study evaluated the anti-fibrotic efficacy of OBT using in vitro models, including TGFβ-induced differentiation in HUCLS, HSC-LX2, and HHSECs, and an in vivo CCl4-induced liver fibrosis model in mice. The in vitro results demonstrated that OBT significantly suppressed the TGFβ-induced upregulation of fibrotic markers at both mRNA and protein levels. In vivo, findings showed that CCl4 treatment caused significant increases in serum liver function markers, inflammatory cell infiltration, collagen deposition, and septal fibrosis in liver tissues. In contrast, OBT treatment attenuated these pathological changes in a dose-dependent manner. Furthermore, assays on oxidative stress indicators revealed that OBT significantly reduced oxidative stress markers and enhanced antioxidant levels. Gene and protein expression analyses showed that OBT suppressed the CCl4-induced elevation of inflammatory cytokines, chemokines, and fibrotic markers compared to the CCl4 control group. Mechanistic studies demonstrated that CCl4 administration activated the ROCK2/p-cofilin/pNFκB signaling pathway, whereas OBT treatment significantly modulated these molecular pathways. OBT alleviates liver inflammation and fibrosis by inhibiting oxidative stress, collagen accumulation, and the ROCK2/NFκB pathway, highlighting its potential as a therapeutic candidate for liver fibrosis.

Keywords:  ROCK-2; cofilin-1; inflammation; liver injury and NFκB; myofibroblasts

DOI:  https://doi.org/10.1016/j.ejphar.2025.178479
MedComm (2020). 2025 Dec;6(12): e70521

Idiopathic Pulmonary Fibrosis: Cellular Heterogeneity, Mechanisms, and Therapeutic Implications.

Lin Zuo, Qiongliang Liu, Defeng Ye, Jiang Fan, Liang Wu.

  Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and irreversible alveolar destruction. Despite advances in antifibrotic therapies, the underlying pathogenic mechanisms remain incompletely understood. Recent multiomic studies have revealed that IPF arises from aberrant communication among epithelial, mesenchymal, immune, and vascular cells within the fibrotic microenvironment, rather than from isolated cellular dysfunction. However, the dynamic intercellular networks and spatiotemporal regulation driving disease progression remain poorly defined. This review integrates recent single-cell RNA sequencing and spatial transcriptomic discoveries to delineate key pathogenic cell populations-including aberrant basaloids and IPF-related alveolar type 2 cells (IR_AT2), CTHRC1+ and meflin+ fibroblasts, and SPP1hi macrophages-and their signaling crosstalk through pathways such as transforming growth factor β(TGF-β), Hippo, and Hedgehog. We further discuss how ECM feedback loops and immune-metabolic remodeling reinforce fibrogenesis and explore emerging therapeutic targets derived from these mechanisms. By synthesizing multidimensional data into a cellular and molecular framework, this review advances the understanding of IPF pathogenesis and provides a conceptual foundation for biomarker-guided precision therapies.

Keywords:  IPF; epithelial cells; fibroblasts; immune cells; scRNA‐seq; spatial transcriptomics

DOI:  https://doi.org/10.1002/mco2.70521
Front Pharmacol. 2025 ;16 1691796

Preclinical research of dihydromyricetin for fibrotic diseases.

Xiao-Chun Wang, Ping Mai, Zuo-Hui Yuan, Zhi-Sheng Qiu.

  Fibrosis is a pathological condition characterized by excessive deposition of extracellular matrix (ECM) components, leading to tissue scarring and progressive organ dysfunction. The effective treatment of fibrotic diseases remains a pressing challenge in medical research. Dihydromyricetin (DHM), a principal bioactive flavonoid derived from Ampelopsis grossedentata, exhibits diverse pharmacological activities, including anti-inflammatory, antioxidant, and autophagy-modulating effects. This comprehensive review systematically analyzes current research to elucidate the molecular mechanisms underlying DHM's anti-fibrotic effects across various organ systems. Additionally, we assessed the compound's chemical properties and toxicological profile. This review aims to advance the understanding of DHM's therapeutic potential for fibrotic diseases, clarify associated molecular mechanisms, and highlight persistent challenges. We also propose new research directions to further decipher the mechanisms of action of this flavonoid, which may facilitate the development of novel therapeutic strategies for fibrotic diseases.

Keywords:  anti-inflammatory; antioxidant; autophagy; dihydromyricetin; fibrosis

DOI:  https://doi.org/10.3389/fphar.2025.1691796
Am J Transl Res. 2025 ;17(11): 8724-8741

MEGF8-driven metabolic reprogramming and immune evasion define a high-risk subtype of endometriosis-associated ovarian cancer.

Bo Zheng, Yu Xia, Yuxuan Feng, Yanqiu Zhang, Haoyue Hu, Bing Jiang, Meng Liu, Nianchao Zhou, Tiantian Wu, Guannan Feng, Chao Huang, Qingxia Meng, Xiaoyan Huang.

   OBJECTIVE: Endometriosis increases ovarian cancer (OC) risk through genetic mutations, chronic inflammation, and hormonal dysregulation, yet the underlying molecular pathways remain underexplored. This study aims to identify endometriosis-associated prognostic biomarkers in OC.
METHODS: Transcriptomic and clinical data from TCGA-OC and GSE53963 were integrated for comprehensive analysis. Prognostic models were constructed using LASSO and Cox regression. Tumor microenvironment (TME) characteristics, immune checkpoints, and drug sensitivity were evaluated with ESTIMATE, CIBERSORT, TIDE, and drug sensitivity profiling. Single-cell RNA sequencing (scRNA-seq, GSE184880) was employed to explore immune and gene expression patterns. MEGF8 function was validated through in vitro assays.
RESULTS: Consensus clustering identified three OC molecular subtypes (A, B, and C), with subtype B showing significantly better overall survival (P = 0.001). Subtype A exhibited a "dual malignant phenotype", characterized by enhanced cell adhesion, epithelial-mesenchymal transition (EMT), TGF-β activation, and an immunosuppressive TME. An 8-gene prognostic model, including MEGF8, effectively stratified patients into high- and low-risk groups, with high-risk patients showing poorer survival, immune evasion, and elevated stromal scores. Drug sensitivity analysis indicated that the low-risk group was more responsive to PI3K/AKT/mTOR and VEGFR inhibitors. MEGF8 was identified as a key regulator in cancer stem cells, promoting tumor progression through metabolic reprogramming and extracellular matrix remodeling. Functionally, MEGF8 knockdown suppressed OC cell proliferation and migration.
CONCLUSION: This study delineated the molecular-immune landscape of OC, established an 8-gene prognostic model, and identified MEGF8 as a potential therapeutic target. The model predicts responses to immunotherapy and targeted therapies, supporting personalized OC management.

Keywords:  Endometriosis; MEGF8; biological behavior; ovarian cancer; prognostic model; single-cell RNA sequencing

DOI:  https://doi.org/10.62347/AOPY5249