Tessier CE, Derrien J, Dupuy AMM
… +20 more, Pelé T, Moquet M, Roul J, Douillard E, El Harrif C, Pinson X, Le Gallo M, Godey F, Tas P, Viel R, Grasset E, Prigent C, Letouzé É, Suzanne P, Dallemagne P, Campone M, Weinberg RA, Lees JA, Juin PP, Guen VJ
EMBO Mol Med
· 2025 Oct · PMID 40859055
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Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by epithelial-mesenchymal transition (EMT). However, EMT in human cancer therape...Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by epithelial-mesenchymal transition (EMT). However, EMT in human cancer therapeutic response remains poorly understood. We developed patient-derived organoids (PDOs) from human triple-negative breast cancer (TNBC) and investigated their response to chemotherapy. We found that chemotherapy treatment kills the bulk of tumor cells in PDOs, but there is selective survival of malignant cells that had activated an EMT program, entered a quasi-mesenchymal, stem cell-like state and display primary cilia. We developed a family of small-molecule inhibitors of ciliogenesis and show that treatment with these inhibitors, or genetic ablation of primary cilia, is sufficient to suppress this chemoresistance via NFκB-induced cell death. We conclude that an EMT-ciliary signaling axis induces chemoresistance in quasi-mesenchymal ciliated stem-like cells to help tumors evade chemotherapy and represents a druggable vulnerability in human TNBC.
Brault L, Voisset E, Desaunay M
… +13 more, Boudet A, Kousteridou P, Letard S, Carbuccia N, Goubard A, Castellano R, Collette Y, Vernerey J, Vigon I, Pasquet JM, Dubreuil P, Lopez S, De Sepulveda P
EMBO Mol Med
· 2025 Oct · PMID 40883610
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The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, r...The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.
Akula MK, Gilis E, Hertens P
… +10 more, Vande Walle L, Sze M, Coudenys J, Incik Y, Khan O, Bergo MO, Elewaut D, Wullaert A, Lamkanfi M, van Loo G
EMBO Mol Med
· 2025 Oct · PMID 40883609
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Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific...Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific deletion of Pggt1b, the gene coding for GGTase-I, leads to spontaneous and severe erosive arthritis in mice; however, the underlying mechanisms remained unclear. In this study, we demonstrate that arthritis in mice with myeloid-specific Pggt1b deficiency is driven by unprenylated GTP-bound small RHO family GTPases, which in turn trigger Pyrin (Mefv) inflammasome activation, GSDMD-dependent macrophage pyroptosis, and IL-1β secretion. We show that although Pggt1b deficiency leads to hyperactivation of RAC1, impaired prenylation alters its proper membrane localization and interaction with effectors, rendering it effectively inactive in vivo. Consequently, unprenylated RHO family signaling promotes Pyrin inflammasome assembly through recruitment to the RAC1 effector IQGAP1. Together, these findings identify a novel inflammatory axis in which non-prenylated RHO GTPase activity promotes spontaneous Pyrin inflammasome activation, pyroptosis, and IL-1β release in macrophages, contributing to inflammatory arthritis in mice.
Fielder SM, Friederich MW, Hock DH
… +37 more, Zhang JR, Valin LM, Rosenfeld JA, Booth KTA, Brown NJ, Rius R, Sharma T, Semcesen LN, Worley KC, Burrage LC, Treat K, Samson T, Govert S, DaCunha S, Yuan W, Chen J, Lesinski J, Hoang H, Morrison SA, Ladha FA, Van Hove RA, Michel CR, Reisdorph R, Tycksen E, Baldridge D, Silverman GA, Soler-Alfonso C, Conboy E, Vetrini F, Emrick L, Craigen WJ, Undiagnosed Diseases Network, Sykes SM, Stroud DA, Van Hove JLK, Schedl T, Pak SC
EMBO Mol Med
· 2025 Oct · PMID 40859057
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ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with de...ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.
EMBO Mol Med
· 2025 Oct · PMID 40859054
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The epithelial–mesenchymal transition (EMT) is a source of cancer cell plasticity and tumour heterogeneity, and is increasingly recognised as a complex and dynamic process (Aiello et al, ; Brown et al, 2022). EMT should...The epithelial–mesenchymal transition (EMT) is a source of cancer cell plasticity and tumour heterogeneity, and is increasingly recognised as a complex and dynamic process (Aiello et al, ; Brown et al, 2022). EMT should not be viewed as a simple linear process, but rather as a continuum of interconnected networks that facilitate cellular changes and adaptations. This fluidity underlies the concept of cellular plasticity, which is crucial in understanding tumour progression and metastasis. Pioneering studies from Robert Weinberg’s lab and others have demonstrated the existence of such states and highlighted the complex nature of EMT and the underlying difficulties in targeting it, which remains one of the overarching challenges in cancer therapy (Dongre & Weinberg, ; Kröger et al, 2019).
Bracq L, Chuat A, Kunz B
… +5 more, Burri O, Guiet R, Duc J, Brandenberg N, van der Goot FG
EMBO Mol Med
· 2025 Oct · PMID 40847216
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Patients with the rare genetic disorder Hyaline Fibromatosis Syndrome (HFS) often succumb before 18 months of age due to severe diarrhea. As HFS is caused by loss-of-function mutations in the gene encoding capillary morp...Patients with the rare genetic disorder Hyaline Fibromatosis Syndrome (HFS) often succumb before 18 months of age due to severe diarrhea. As HFS is caused by loss-of-function mutations in the gene encoding capillary morphogenesis gene 2 (CMG2), these symptoms highlight a critical yet unexplored role for CMG2 in the gut. Here, we demonstrate that CMG2 knockout mice exhibit normal colon morphology and no signs of inflammation until the chemical induction of colitis. In these conditions, the colons of knockout mice do not regenerate despite previously experiencing similarly severe colitis, due to an inability to replenish their intestinal stem cell pool. Specifically, CMG2 knockout impairs the transition from fetal-like to Lgr5+ adult stem cells, which is associated with a defect in ß-catenin nuclear translocation. Based on our findings, we propose that CMG2 functions as a context-specific modulator of Wnt signaling, essential for replenishing the pool of intestinal stem cells following injury. This study provides new insights into the molecular mechanisms underlying lethal diarrhea in HFS and offers a broader understanding of fetal-like regenerative responses.
EMBO Mol Med
· 2025 Oct · PMID 40847215
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Polarized columnar epithelial cells form a delicate yet highly effective, single-cell-thick barrier that lines the intestine and other mucosal surfaces. Their function is to separate and actively affect vastly different...Polarized columnar epithelial cells form a delicate yet highly effective, single-cell-thick barrier that lines the intestine and other mucosal surfaces. Their function is to separate and actively affect vastly different physiological compartments—forming a challenging cellular interface between the host and the outside world. In the intestine, many potential dangers to cell function and survival transit the luminal gut environment—amplified by a hugely dense microbial community colonizing the mucosal surface.
Campos J, McMurray JL, Certo M
… +10 more, Hardikar K, Morse C, Corfield C, Weigand BM, Yang K, Shoaran M, Otto TD, Neil D, Maffia P, Mauro C
EMBO Mol Med
· 2025 Oct · PMID 40847214
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Atherosclerosis is characterized by the accumulation of lipids and immune cells in the arterial wall, leading to the narrowing and stiffening of blood vessels. Innate and adaptive immunity are involved in the pathogenesi...Atherosclerosis is characterized by the accumulation of lipids and immune cells in the arterial wall, leading to the narrowing and stiffening of blood vessels. Innate and adaptive immunity are involved in the pathogenesis of human atherosclerosis. However, spatial organization and roles of immune cells during disease progression remain poorly understood. A better understanding of the immune response's contribution to atherosclerosis progression could unveil novel therapeutic targets to mitigate plaque development and rupture, ultimately reducing cardiovascular events burden. Here, we utilised GeoMx® and CosMx™ technologies to analyse serial sections of human coronary arteries from patients with varying degrees of atherosclerotic lesion severity. Our work comprises a series of investigations and integrates findings from both datasets, including pathway analyses, cell typing, and neighbourhood analysis. This workflow highlights the power of combining these spatial transcriptomics platforms to elucidate biological processes at the single-cell level. Our approach unbiasedly identifies molecules and pathways of relevance to support the understanding of atherosclerosis pathogenesis and assess the potential for novel therapies.
Freytag D, Giorgiutti S, Hopsomer G
… +14 more, Wadier N, Depauw S, Mertz P, Augé F, Carapito R, Couillin I, Korganow AS, Pala F, Bosticardo M, Notarangelo LD, Rieux-Laucat F, Riteau N, Kirstetter P, Soulas-Sprauel P
EMBO Mol Med
· 2025 Sep · PMID 40804163
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STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, part...STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, partly due to impaired thymic development. To investigate the mechanisms of peripheral T cell dysfunctions, we analyzed transcriptomic and phenotypic profiles of splenic T cells from these mice. We found a terminally exhausted T cell phenotype, established early in life upon entry into the periphery, independent of type I interferons and intrinsic STING activation in T cells or stromal cells. Mechanistically, naive T cells in the lymphopenic periphery experienced heightened stimulation of the IL-7 receptor and TCR, including NFAT pathway, a key factor in T cell exhaustion. Transplantation of STING GOF hematopoietic stem cells with wild-type bone marrow prevented exhaustion in this non-lymphopenic context, placing lymphopenia as a key driver. T cell exhaustion was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results highlight T cell exhaustion induced by lymphopenia and could have important implications for the management of patients with severe immune deficiencies.
Pérez MJ, Colombo RB, Real SM
… +4 more, Branham MT, Laurito SR, Moraes CT, Mayorga L
EMBO Mol Med
· 2025 Sep · PMID 40790102
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Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising s...Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising strategy, though it currently faces challenges. Previous research showed that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, through changes in DNA methylation, absent or less important for subtle mitochondrial impairment. Therefore, we hypothesized that targeting nuclear DNA methylation could impair cells with high-mutant mtDNA load while sparing those with lower levels, reducing overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513 G > A and m.8344 A > G-at varying heteroplasmies, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern critical for the survival of high-heteroplasmy cells but not for low-heteroplasmy ones. Treatment with FDA-approved DNA methylation inhibitors selectively impacted high-heteroplasmy cybrids and reduced heteroplasmy. These findings were validated in cultured cells and xenografts. Our findings highlight nuclear DNA methylation as a key regulator of heteroplasmic cell survival and a potential therapeutic target for mitochondrial diseases.
Merchant MK, de Paula Souza J, Abdelkarim S
… +20 more, Chakraborty S, Nasser Neto TA, Gutierrez Manchay KI, de Melo Jorge DM, do Nascimento VA, Sun Y, Caroe ER, Eyssen LEA, Rudd JS, Ribeiro Piauilino IC, Damasceno Pinto S, Pereira da Silva MH, Rocha do Nascimento F, Naveca FG, Proenca-Modena JL, da Silva LLP, Pinto de Figueiredo RM, Owens RJ, Arruda E, Graham SC
EMBO Mol Med
· 2025 Sep · PMID 40790101
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Oropouche fever is a neglected tropical disease caused by the orthobunyavirus Oropouche virus (OROV). A recent OROV epidemic caused by a novel reassortant has seen infections across an expanded geographical range, with d...Oropouche fever is a neglected tropical disease caused by the orthobunyavirus Oropouche virus (OROV). A recent OROV epidemic caused by a novel reassortant has seen infections across an expanded geographical range, with deaths of healthy adults plus vertical transmission leading to pregnancy loss. OROV research and epidemiology is hampered by a paucity of available tools for serology and molecular virology. We have purified recombinant OROV nucleoprotein and the spike region of the viral surface glycoprotein Gc. These antigens detect seroconversion following experimental infection of animals in indirect ELISA, confirming their antigenic authenticity. They stimulate the production of high neutralising antibody titres in animals, highlighting their promise as immunogens for vaccination. We developed a nanobody-based sandwich ELISA that can detect OROV antigens in human clinical serum samples with high efficiency, and we show that nanobodies directed against OROV Gc spike can potently neutralise infection by both historical OROV strains and the newly emerged reassortant. Our protein-based reagents will accelerate OROV research and highlight the utility of protein-based tools for future OROV vaccines and point-of-care diagnostic devices.
Jo H, Munoz S, Dalvi A
… +3 more, Yang W, Morozova E, Glasgow SM
EMBO Mol Med
· 2025 Sep · PMID 40770117
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Glioblastoma Multiforme (GBM) is a highly malignant brain cancer with limited effective therapies. Neurodevelopmental pathways have been implicated in glioma formation, with key neurodevelopmental regulators being re-exp...Glioblastoma Multiforme (GBM) is a highly malignant brain cancer with limited effective therapies. Neurodevelopmental pathways have been implicated in glioma formation, with key neurodevelopmental regulators being re-expressed or co-opted during glioma tumorigenesis. Here we identified a serine/threonine kinase, NUAK family kinase 2 (NUAK2), as a fetal oncogene in mouse and human brains. We found robust expression of NUAK2 in the embryonic brain that decreases throughout postnatal stages and then is re-expressed in malignant gliomas. However, the role of NUAK2 in GBM tumorigenesis remains unclear. We demonstrate that CRIPSR-Cas9 mediated NUAK2 deletion in GBM cells results in suppression of proliferation, while overexpression leads to enhanced cell growth in both in vitro and in vivo models. Further investigation of the downstream biological processes dysregulated in the absence of NUAK2 reveals that NUAK2 modulates extracellular matrix (ECM) components to facilitate migratory behavior. Lastly, we determined that pharmaceutical inhibition of NUAK2 is sufficient to impede the proliferation and migration of malignant glioma cells. Our results suggest that NUAK2 is an actionable therapeutic target for GBM treatment.
Landry C, Costanzo JP, Mitne-Neto M
… +5 more, Zatz M, Schaffer AE, Hatzoglou M, Muotri AR, Miranda HC
EMBO Mol Med
· 2025 Sep · PMID 40764463
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Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS)....Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.
Gomes KP, Korodimas J, Liu E
… +6 more, Patel N, Yang X, Goruk S, Munhoz J, Field CJ, Gibson SB
EMBO Mol Med
· 2025 Sep · PMID 40759794
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Lymphedema is a chronic lymphatic disorder characterized by persistent tissue swelling, pain, and recurrent infections, often secondary to cancer treatment, surgery, or obesity. Obesity-associated increases in saturated...Lymphedema is a chronic lymphatic disorder characterized by persistent tissue swelling, pain, and recurrent infections, often secondary to cancer treatment, surgery, or obesity. Obesity-associated increases in saturated fatty acids (SFAs) have been linked to lipotoxicity. In this study, patients with secondary lymphedema showed a significantly lower plasma polyunsaturated to saturated fatty acid (PUFA/SFA) ratio compared to BMI-matched controls. Stearic acid, a common dietary SFA, induced apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress in human lymphatic endothelial cells. In a mouse model, a short-term high-SFA diet was used to lower the plasma PUFA/SFA ratio, which worsened tail swelling, oxidative stress, ER stress, and tissue damage following lymphatic injury. Switching to a standard chow diet after surgery prevented these effects. Patients with lymphedema also exhibited elevated levels of fatty acid-binding protein 4 (FABP4), a lipid chaperone associated with metabolic stress. FABP4 inhibition reduced stearic acid-induced cell death in vitro and mitigated tissue damage in vivo. These findings suggest a pathogenic role for SFAs and support dietary modulation and FABP4 inhibition as potential therapeutic strategies for lymphedema.
Hunter B, Zhang Y, Harney D
… +15 more, McEwen H, Koay YC, Pan M, Malecki C, Khor J, Hume RD, Guglielmi G, Walker A, Dutta S, Rajagopal V, Don A, Larance M, O'Sullivan JF, Yang JYH, Lal S
EMBO Mol Med
· 2025 Sep · PMID 40759793
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Ischaemic cardiomyopathy is the most common cause of heart failure and often coexists with diabetes mellitus, which worsens patient symptom burden and outcomes. Yet, their combined effects are seldom investigated and are...Ischaemic cardiomyopathy is the most common cause of heart failure and often coexists with diabetes mellitus, which worsens patient symptom burden and outcomes. Yet, their combined effects are seldom investigated and are poorly understood. To uncover the influencing molecular signature defining ischaemic cardiomyopathy with diabetes, we performed multi-omic analyses of ischaemic and non-ischaemic cardiomyopathy with and without diabetes against healthy age-matched donors. Tissue was sourced from pre-mortem human left ventricular myocardium. Fatty acid transport and oxidation proteins were most downregulated in ischaemic cardiomyopathy with diabetes relative to donors. However, the downregulation of acylcarnitines, perilipin, and ketone body, amino acid, and glucose metabolising proteins indicated lipid metabolism may not be entirely impaired. Oxidative phosphorylation, oxidative stress, myofibrosis, and cardiomyocyte cytoarchitecture also appeared exacerbated principally in ischaemic cardiomyopathy with diabetes. These findings indicate that diabetes confounds the pathological phenotype in heart failure, and the need for a paradigm shift regarding lipid metabolism.
Pollock C, Wang X, Alsaraji H
… +15 more, Menassa J, Mbogo G, Angage D, Richards B, Glab J, Datta KK, Theodoridis L, Petrovski S, Donner D, Lizarme-Salas Y, Du XJ, Foley M, Smith BJ, Abbott B, Puthalakath H
EMBO Mol Med
· 2025 Sep · PMID 40759792
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Heart failure presents a critical health challenge with a 5-year mortality rate of up to 50%. Conventional treatments often lead to bradycardia or hypotension due to their impact on patient hemodynamics. To address this...Heart failure presents a critical health challenge with a 5-year mortality rate of up to 50%. Conventional treatments often lead to bradycardia or hypotension due to their impact on patient hemodynamics. To address this issue, we utilized high-throughput drug screening combined with structure-activity relationship-based medicinal chemistry to develop a novel drug-like compound that effectively blocks the β-adrenergic receptor (β-AR) mediated apoptosis pathway. This compound demonstrated both safety and efficacy in pre-clinical mouse models without adversely affecting cardiac output. Through thermal proteome profiling mass spectrometry, we identified the compound's target as Wdr3, a regulator of the Hippo signaling pathway. This target identification was further validated using CRISPR-based knockout experiments. Our findings provide a valuable framework for the development of hemodynamically neutral therapies aimed at treating systolic heart failure.
Nouruzi S, Kobelev M, Tabrizian N
… +2 more, Gleave M, Zoubeidi A
EMBO Mol Med
· 2025 Sep · PMID 40759791
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Significant advances in prostate cancer (PCa) treatment have occurred through the integration of molecular biomarkers and imaging with targeted therapies. While androgen receptor pathway inhibition (ARPI) remains the cor...Significant advances in prostate cancer (PCa) treatment have occurred through the integration of molecular biomarkers and imaging with targeted therapies. While androgen receptor pathway inhibition (ARPI) remains the cornerstone of PCa therapy, the current therapeutic landscape has expanded to include a broader range of targeted agents, alongside emerging approaches that leverage disease-specific vulnerabilities. Molecular profiling has enabled the exploration of diverse therapeutic modalities, including epigenetic regulators, immune-modulating agents, metabolic pathways, kinases, and cell surface proteins. Despite this progress, further research is needed to address tumour heterogeneity and treatment-resistant phenotypes. As ARPI use moves earlier in the disease course and novel agents are incorporated into standard care, prolonging disease control may also reshape emergent resistant phenotypes and disease progression trajectories. This evolving context underscores the need to revisit agents that may now show efficacy in new therapeutic settings or when paired with complementary strategies. Here, we review the current treatment framework in PCa and highlight novel approaches and targets poised to transform clinical care.
EMBO Mol Med
· 2025 Sep · PMID 40745212
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Fibrosis, marked by excessive extracellular matrix deposition, underlies the progression of major organ pathologies, including cardiac and skeletal muscle diseases. Central to fibrotic remodeling is the persistent activa...Fibrosis, marked by excessive extracellular matrix deposition, underlies the progression of major organ pathologies, including cardiac and skeletal muscle diseases. Central to fibrotic remodeling is the persistent activation of myofibroblasts, orchestrated by profibrotic mediators such as transforming growth factor-beta (TGF-β). SMAD7, a key inhibitor of TGF-β signaling, has emerged as both an antifibrotic effector and a modulator of immune and tissue remodeling responses. New insights reveal that SMAD7 exerts cell-specific antifibrotic effects, particularly within myofibroblasts, limiting macrophage-driven fibrogenesis through paracrine mechanisms. Moreover, the integration of SMAD7 modulation into engineered cellular therapies, such as CAR-T cells, highlights its potential to enhance regenerative outcomes and immune resilience against fibrosis. Here, we review the expanding role of SMAD7 in cardiac, skeletal muscle, and vascular tissues, emphasizing its promise as a therapeutic target for reprogramming fibrosis, promoting tissue repair, and restoring organ function in chronic disease settings.
EMBO Mol Med
· 2025 Sep · PMID 40745211
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Sixteen Gα-subunits transduce hundreds of G protein-coupled receptors and control countless cellular activities. Mutations in respective GNA genes underlie developmental, oncological, metabolic, neurological, and other p...Sixteen Gα-subunits transduce hundreds of G protein-coupled receptors and control countless cellular activities. Mutations in respective GNA genes underlie developmental, oncological, metabolic, neurological, and other pathologies. In addition to classical loss-of-function (LOF) and gain-of-function (GOF) mutations (the former represented by gene deletions/truncations, the latter by specific GTP hydrolysis-deficient mutations), multiple pathogenic dominant missense variants have been discovered in GNA genes, and their numbers constantly increase through advanced genetic diagnostics. While these mutations often have confusing features of hypomorphic, dominant-negative, and GOF mutations, many of the pathogenic Gαo (and by inference, other Gα-subunit) variants have recently emerged as neomorphic, i.e., leading to the creation of novel dominant pathogenic functions. Cross-family analysis of these missense variants scattered across GNA genes permits establishing mutational signatures underlying a wide range of Gα-pathies. These mutation patterns have a strong predictive power in the following aspects. First, new dominant mutations in further GNA genes will be discovered in rare diseases. Second, unifying mechanisms of pathogenic dominance emerge in different Gα-subunits. And third, drug(s) acting against some Gα-pathies may prove effective against others.