Biology subjects

Simpson, K.

Publications and source records attributed to Simpson, K..

At least 19 recordsLinked to original sources

bioRxiv2026

The chemorepellent effect of metformin limits bacterial penetration into mammalian mucus by altering bacterial motility

Metformin improves metabolic health and remodels the intestinal microbiota, yet how these microbial changes contribute to therapeutic benefits remains incompletely understood. We combined human metagenomics, quantitative analyses of bacterial behavior and ex vivo mucus models to investigate how metformin modulates host-microbiota interactions. Human metagenomics revealed metformin-associated enrichment of chemotaxis- and motility-related genes. At millimolar concentrations, metformin acted as a bacterial chemorepellent, an effect abolished by deletion of the chemotaxis regulator CheY and dependent on the chemoreceptor Tsr. Direct metformin exposure or fecal water from metformin-treated individuals reduced bacterial penetration into mucin, an effect reproduced in intestinal mucus from pigs fed a moderate-fat diet. Metformin treatment was further associated with reduced fecal flagellin activity and increased anti-flagellin IgA. Together, these findings identify bacterial chemotaxis as a target of metformin and reveal a mechanism by which metformin may limit bacterial access to the intestinal mucus barrier.

microbiology↗

bioRxiv2026

Cell cycle dependent regulation of mRNA export in response to replication stress

Nuclear export of mRNA is extensively coupled to transcription and processing of mRNA. How mRNA export is mechanistically regulated remains poorly understood. Here, we uncover a physical checkpoint at nuclear speckles that regulates mRNA export during DNA replication in S-phase of the cell cycle. Unbiased screening approaches identify WEE1 and CHK1 as novel mRNA export regulators. mRNA export complexes are recruited to sites of replication stress in S-phase. WEE1 inhibition prematurely activates CDK1 and PLK1, leading to accumulation of R-loop associated mRNA in large nuclear speckles, with late markers of replication stress present around their periphery. This recruitment is dependent on CDK1 activity. Phosphorylation of ALYREF by CDK1 and PLK1 regulates nuclear speckle accumulation of mRNA following replication stress. mRNA export factors including ALYREF are subsequently mis-localised from these speckles, preventing nuclear export of R-loop associated mRNA. Thus, WEE1, CDK1 and PLK1 enforce a cell cycle regulated checkpoint at nuclear speckles that serves to protect the cell from major sources of genome instability by ensuring that R-loop associated mature mRNA is not exported to the cytoplasm.

molecular biology↗

bioRxiv2026

Targeting DNA Methylation Reactivates Type I Interferon Signalling in Bone-Metastatic Breast Cancer

Bone metastasis remains a major clinical challenge in advanced breast cancer. Downregulation of type I interferon signalling, a critical immunomodulatory pathway in anti-cancer immunity and disease progression, is a defining feature of this process. Here, we utilised an IFN-reporter system to perform unbiased epigenetic compound screens to identify agents that could restore type I IFN signalling. This screen identified Decitabine, a DNA hypomethylating agent, that enhanced tumor immunogenicity across a broad range of mouse and human breast cancer cell lines, including bone-derived lines. Mechanistically, suppression of interferon-stimulated genes is highly correlated with elevated DNMT1 expression in bone metastasis compared with primary tumor, in both mouse models and matched human samples. Decitabine treatment was sufficient to reactivate interferon stimulated genes in bone-derived 4T1.2 cell lines via hypomethylation of type I interferon pathway gene promoter regions. Correspondingly, in the syngeneic 4T1.2 metastasis mouse model, Decitabine treatment conferred a survival benefit and reduced metastatic potential, particularly in bone. Our findings reveal DNA methylation as a key regulator of the transcriptional programs underlying bone metastasis, providing mechanistic insight into how Decitabine reactivates type I interferon signalling and reduces metastatic potential, highlighting epigenetic reprogramming as a promising approach for targeting metastatic breast cancer. STATEMENT OF SIGNIFICANCEBone metastasis remains a major clinical challenge and a key mechanism of progression to bone is the suppression of tumor-inherent type I interferon signalling. We identified Decitabine, a DNA hypomethylating agent, as a promising therapeutic agent to enhance tumor immunogenicity across a broad range of breast cancer cell lines, including bone metastasis-derived lines. Our findings support DNA methylation as a key regulator of transcriptional programs associated with bone metastatic progression, and provide mechanistic insight into how Decitabine reactivates type I interferon signalling and reduces metastatic potential in vivo. These results highlight epigenetic reprogramming as a promising approach for targeting metastatic breast cancer.

Cancer Biology↗

bioRxiv2025

Disruption of IgA-mediated aggregation at weaning favors mucus encroachment by commensal bacteria

Disruption of the gut mucus barrier is a critical step in the development of infec-tious or chronic inflammatory diseases. However, there are no clear links between developmental stages, diet, and the mechanical and biochemical properties of mucus. The transition from suckling to weaning is a pivotal stage in the devel-opment of the mucus barrier in mammals, with significant implications for the health and morbidity of mammalian infants. Here, using a novel microfluidic device, we investigate the penetration and organizational properties of motile Escherichia coli bacteria at the mucus interface using purified intestinal mucus collected from cohorts of piglets before and after weaning. In weaned piglets, E. coli penetrate more than 100 {micro}m into the mucus, a distance greater than the physiological thickness of the mucus layer in vivo. In contrast, for suckling piglets significant bacterial aggregation is observed at the interface, hindering the pene-tration process. Using the supernatant obtained from purified mucus of suckling piglets, we were able to restore bacterial aggregation in weaned piglet mucus and limit penetration. Interestingly, we also achieved the same result using purified human breast milk immunoglobulin A (IgA), which is known to promote bacterial aggregation. Our results emphasize the importance of mucosal immunoglobulin A (IgA) specificity in relation to the mothers immunological history, which is primarily transmitted through breast milk and lost during weaning. This also might explain why the suckling/weaning transition is, among other issues, a crit-ical window associated with a high incidence of gastrointestinal infections, before autologous IgA-mediated definite protection is acquired. Studying bacterial pen-etration in complex fluids using this new in vitro microfluidic device will pave the way for future research and the development of predictive tools for use in medical research trials.

microbiology↗

bioRxiv2025

SOX9 plays an essential role in myofibroblast driven hepatic granuloma integrity and parenchymal repair during schistosomiasis-induced liver damage

Schistosomiasis is a neglected, and potentially lethal, parasitic disease that affects hundreds of millions of people worldwide. As part of the schistosome lifecycle, parasite eggs accumulate within the liver where they evoke intense granulomatous pathology, typified by a dense extracellular matrix (ECM) barrier, which serves to contain toxic egg secretions. In severe cases, this progressive and irreversible egg-evoked ECM deposition can lead to pathological scarring, impaired liver function and lethality. Thus, identifying the core regulators that govern ECM deposition may aid discovery of new therapeutic targets for schistosomiasis. The transcription factor Sex determining region Y-box 9 (Sox9) is a known regulator of pathological scaring. We found that, following Schistosoma mansoni infection, SOX9 was ectopically expressed in myofibroblasts within the granuloma and in surrounding hepatocytes. In the absence of SOX9, granuloma size was significantly diminished, and mice failed to produce a robust ECM barrier around eggs, resulting in more diffuse liver injury and scattered distribution of immune cells. Immunologically, SOX9 loss in both naive and infected mice led to an increase in hepatic neutrophil and monocyte proportions, with the expansion of Ly6clo monocyte populations in infected SOX9 deficient mice only. Infected SOX9-deficient mice also displayed exaggerated Type 2 inflammation, including pronounced eosinophilia. These data highlight the importance of SOX9 for intact hepatic granuloma formation during schistosomiasis and suggest SOX9 or its related factors may provide attractive future targets for meeting the clinical need to limit and/or reverse fibrotic disease. Author SummaryMammalian infection with schistosome worms results in the deposition of parasite eggs in the liver, where they secrete organ damaging toxins. In response, the liver generates a cellular granuloma barrier rich in extracellular matrix to limit these secretions and protect the overall organ. As in other liver injuries, SOX9 becomes progressively expressed in multiple cell types during the time course of schistosome infection. To understand the role of SOX9 in the liver response to schistosomes we utilised a global SOX9 deficient mouse model. These mice show reduced and disorganised granuloma formation during schistosome infection, with disrupted hepatic immune profiles. This suggests that SOX9 is required to form a robust and coordinated granuloma barrier that limits liver damage in this important but neglected parasitic disease.

immunology↗

bioRxiv2024

Copper induces p53 unfolding in cancer cells, resulting in invasion and chemoresistance

Copper has been shown to play an important role in cancers, enhancing cell proliferation, remodelling the microenvironment and enhancing the function of oncogenes. Here we show that copper turns the tumour suppressor p53 protein into a pro-oncogenic protein. Mutations in the TP53 gene often lead to expression of various mutant p53 proteins. Mutant proteins often lose some or all wild type function and gain novel pro-tumourigenic functions, which can be partially attributed to protein unfolding. Here we show that copper accumulates in tumours, unfolds WTp53 and promotes chemoresistance. Unfolding of WT p53 results in interaction with mutant p53-specific interacting proteins TAp63 and Ago2 and promotes invasion. Interestingly, partially-functional p53 mutants that are frequently observed in lung cancers, are more affected by copper than WTp53. Our results suggest that small increases in copper impair WT p53 function and augment mutant p53 function, which could partially be restored by the chelator Trien.

cancer biology↗

bioRxiv2024

Circulating tumor cells shed large extracellular vesicles in capillary-sized bifurcations

Circulating tumor cells (CTCs) and their clusters are the drivers of metastasis, but we have an incomplete understanding of how they interact with capillary beds. Using microfluidic models mimicking human capillary bifurcations, we observed cell size- and bifurcation-dependent shedding of nuclei-free fragments by patient CTCs, CTC-derived explant cells and numerous cancer cell lines. Shedding reduced cell sizes up to 61%, facilitating their transit through bifurcations. We demonstrated that shed fragments were a novel subclass of large extracellular vesicles (LEVs), "shearosomes", that require shear stress for their biogenesis and whose proteome was associated with immune-related pathways. Shearosomes exhibited functions characteristic of previously identified EVs including cell-directed internalization by endothelial and immune cells, and intercellular communication abilities such as disruption of endothelial barrier integrity, polarization of monocytes into M2 tumor-promoting macrophages and interactions between endothelial and immune cells. Cumulatively, these findings suggest that CTCs shed shearosomes in capillary beds that drive key processes involved in the formation of pre-metastatic niches.

cancer biology↗

bioRxiv2024

SOX9-regulated matrix proteins predict poor outcomes in patients with COVID-19 and pulmonary fibrosis

Pulmonary fibrosis is an increasing and major cause of death worldwide. Understanding the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis may lead to urgently needed diagnostic and prognostic strategies for the disease. SOX9 is a core transcription factor that has been associated with fibrotic disease, however its role and regulation in acute lung injury and/or fibrosis have not been fully defined. In this study we apply a hypothesis based approach to uncover unique SOX9-protein signatures associated with both acute lung injury and fibrotic progression. Using in vivo models of lung injury in the presence or absence of SOX9, our study shows SOX9 is essential to the damage associated response of alveolar epithelial cells from an early time-point in lung injury. In parallel, as disease progresses, SOX9 is responsible for regulating tissue damaging ECM production from pro-fibrotic fibroblasts. In determining the in vivo role of SOX9 we identified secreted ECM components downstream of SOX9 as markers of acute lung injury and fibrosis. To underscore the translational potential of our SOX9-regulated markers, we analysed serum samples from acute COVID19, post COVID19 and idiopathic pulmonary fibrosis (IPF) patient cohorts. Our hypothesis driven SOX9-panels showed significant capability in all cohorts at identifying patients who had poor disease outcomes. This study shows that SOX9 is functionally critical to disease in acute lung injury and pulmonary fibrosis and its regulated pathways have diagnostic, prognostic and therapeutic potential in both COVID19 and IPF disease.

molecular biology↗

bioRxiv2023

Microfabrication-based engineering of biomimetic dentin-like constructs to simulate dental aging

1.Human dentin is a highly organized dental tissue displaying a complex microarchitecture consisting of micrometer-sized tubules encased in a mineralized type-I collagen matrix. As such, it serves as an important substrate for the adhesion of microbial colonizers and oral biofilm formation in the context of dental caries disease, including root caries in the elderly. Despite this issue, there remains a current lack of effective biomimetic in-vitro dentin models that facilitate the study of oral microbial adhesion by considering the surface architecture at the micro- and nanoscales. Therefore, the aim of this study was to develop a novel in-vitro microfabricated biomimetic dentin surface that simulates the complex surface microarchitecture of exposed dentin. For this, a combination of soft lithography microfabrication and biomaterial science approaches were employed to construct a micropitted PDMS substrate functionalized with mineralized type-I collagen. These dentin analogues were subsequently glycated with methylglyoxal (MGO) to simulate dentin matrix aging in-vitro and analyzed utilizing an interdisciplinary array of techniques including atomic force microscopy (AFM), elemental analysis, and electron microscopy. AFM force-mapping demonstrated that the nanomechanical properties of the biomimetic constructs were within the expected biological parameters, and that mineralization was mostly predominated by hydroxyapatite deposition. Finally, dual-species biofilms of Streptococcus mutans and Candida albicans were grown and characterized on the biofunctionalized PDMS microchips, demonstrating biofilm specific morphologic characteristics and confirming the suitability of this model for the study of early biofilm formation under controlled conditions. Overall, we expect that this novel biomimetic dentin model could serve as an in-vitro platform to study oral biofilm formation or dentin-biomaterial bonding in the laboratory without the need for animal or human tooth samples in the future.

bioengineering↗

bioRxiv2023

A spatial map of human liver cirrhosis reveals the patho-architecture and gene signatures associated with cell state transitions during liver disease

Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis. Through multi-modal data integration, we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory from hepatocytes to cholangiocytes associated with disease remodelling. We identify pro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach provides a spatial atlas of gene regulation and defines molecular signatures associated liver disease for targeted therapeutics or as early diagnostic markers of progressive liver disease.

genomics↗

bioRxiv2023

Spatial biology of Ising-like synthetic genetic networks

BackgroundUnderstanding how spatial patterns of gene expression emerge from the interaction of individual gene networks is a fundamental challenge in biology. Developing a synthetic experimental system with a common theoretical framework that captures the emergence of short- and long-range spatial correlations (and anti-correlations) from interacting gene networks could serve to uncover generic scaling properties of these ubiquitous phenomena. ResultsHere, we combine synthetic biology, statistical mechanics models and computational simulations to study the spatial behavior of synthetic gene networks (SGNs) in Escherichia coli quasi-2D colonies growing on hard agar. Guided by the combined mechanisms of the contact process lattice simulation and two-dimensional Ising model (CPIM), we describe the spatial behavior of bi-stable and chemically-coupled SGNs that self-organize into patterns of long-range correlations with power-law scaling or short-range anti-correlations. These patterns, resembling ferromagnetic and anti-ferromagnetic configurations of the Ising model near critical points, maintain their scaling properties upon changes in growth rate and cell shape. ConclusionsOur findings shed light on the spatial biology of coupled and bistable gene networks in growing cell populations. This emergent spatial behavior could provide insights into the study and engineering of self-organizing gene patterns in eukaryotic tissues and bacterial consortia.

synthetic biology↗

bioRxiv2023

PAK1-dependant mechanotransduction enables myofibroblast nuclear adaptation and chromatin organisation during fibrosis

Myofibroblasts are responsible for scarring and organ stiffness during fibrosis. The scar propagates mechanical signals inducing a radical transformation in myofibroblast cell state linked to an increasingly pro-fibrotic phenotype. Here, we have discovered mechanical stress from progressive scarring induces nuclear softening and de-repression of heterochromatin. The parallel loss of H3K9Me3 enables a permissive state for distinct chromatin accessibility and profibrotic gene regulation. By integrating chromatin accessibility profiles (ATAC sequencing) we provide insight into the transcription network and open chromatin landscape underlying the switch in profibrotic myofibroblast states, emphasizing mechanoadaptive pathways linked to PAK1 as key drivers. Through genetic manipulation in liver and lung fibrosis, uncoupling PAK1-dependant signaling impaired the mechanoadaptive response in vitro and dramatically improved fibrosis in vivo. Moreover, we provide human validation for mechanisms underpinning PAK1 mediated mechanotransduction in liver and lung fibrosis. Collectively, these observations provide new insight into the nuclear mechanics driving the profibrotic chromatin landscape in fibrosis, highlighting actomyosin-dependent mechanisms linked to chromatin organisation as urgently needed therapeutic targets in fibrosis.

cell biology↗

bioRxiv2023

Systematic Nature Positive Markets

Despite decades of global commitments, and increasingly urgent warning of environmental instability, the demand for land to support economic production is still increasing. Isolated and disorganized actions will not be enough to avert ecosystem failures. As many developers are already required to compensate for their ecological impacts through restoration, many see markets trading biodiversity credits as a financial mechanism to counteract degradation and drive investment in conservation. The challenge stems from a desire to recognize the multidimensional nature of biodiversity that contributes to ecosystem integrity without making suitable offsets intractable to supply. Instead, most regulators have opted to streamline ecological assessment, and undermine ecological rigour, in favour of promoting offset supply and economic efficiency. As a result, all evidence suggests offset trading programs have so far failed to mitigate losses, let alone support "nature positive" outcomes. To overcome this disconnect, and support more effective and equitable biodiversity markets, we propose credits be defined by the irreplaceability of a site, a metric long-established in the domain of systematic conservation planning. Irreplaceability avoids the limitations of like-for-like trading, reduces costs of offsetting to developers and society, ensures farmers willing to sell are fairly rewarded for loss of earnings, and that sites critical to achieving conservation goals are safeguarded. We developed an ecological-economic model of a biodiversity offset market to demonstrate irreplaceability guarantees no net loss of biodiversity and is the most efficient metric for guiding investment toward the recovery of Nature.

ecology↗

bioRxiv2021

Serum CSF1 levels are elevated in patients following partial hepatectomy and acetaminophen induced acute liver failure: Reanalysis of previous data

A previous study analysed serum CSF1 concentration in patients who had undergone partial hepatectomy and patients with acute liver failure (ALF) induced by acetaminophen. A correlation between low CSF1 and poor prognosis was reported in ALF. In May 2018, an allegation of research misconduct was made against the second author of the published study, D.J.Antoine, who carried out the CSF1 analysis. The current study describes the independent reanalysis of circulating CSF1 concentration in sera from the same patient cohorts. Patient serum CSF1 levels increased following partial hepatectomy. By contrast to the published report, serum CSF1 concentration was greatest in ALF patients who died compared to survivors. The results confirm the relationship between liver injury and circulating serum CSF1.

immunology↗

bioRxiv2021

Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer

Patients with colorectal cancer (CRC) frequently develop liver metastases during the course of their disease. A substantial proportion of them receive neoadjuvant FOLFOX (5-Fluorouracil, Oxaliplatin, Leucovorin) prior to surgery in an attempt to enable successful surgical removal of their metastases and to reduce the risk of recurrence. Yet, the majority of patients progress during treatment or recur following surgery, and molecular mechanisms that contribute to FOLFOX resistance remain poorly understood. Here, using a combination of phenotypic, transcriptomic and genomic analyses of both tumor samples derived from patients with metastatic CRC and matching patient-derived tumor organoids (PDTOs), we characterize a novel FOLFOX resistance mechanism and identify inhibitors that target this mechanism to resensitize metastatic organoids to FOLFOX. Resistant PDTOs, identified after in vitro exposure to FOLFOX, exhibited elevated expression of E2F pathway, S phase, G2/M and spindle assembly checkpoints (SAC) genes. Similar molecular features were detected in CRLM from patients with progressive disease while under neoadjuvant FOLFOX treatment, highlighting the relevance of this finding. FOLFOX resistant PDTOs displayed inactivating mutations of TP53 and exhibited transcriptional features of P53 pathway downregulation. We found that they accumulated in early S-phase and underwent significant DNA damage during FOLFOX exposure, thereafter arresting in G2/M while they repaired their DNA after FOLFOX withdrawal. In parallel, results of a large kinase inhibitor screen indicated that drugs targeting regulators of the DNA damage response, G2M checkpoint and SAC had cytotoxic effects on PDTOs generated from patients whose disease progressed during treatment with FOLFOX. Corroborating this finding, CHK1 and WEE1 inhibitors were found to synergize with FOLFOX and sensitize previously resistant PDTOs. Additionally, targeting the SAC master regulator MPS1 using empesertib after exposure to FOLFOX, when cells accumulate in G2M, was also very effective to kill FOLFOX-resistant PDTOs. Our results indicate that targeted and timely inhibition of specific cell cycle checkpoints shows great potential to improve response rates to FOLFOX in patients with metastatic CRC, for whom therapeutic alternatives remain extremely limited.

cancer biology↗

bioRxiv2021

Social prediction modulates activity of macaque superior temporal cortex

The ability to attribute thoughts to others, also called theory of mind (TOM), has been extensively studied. Computationally, the basis of TOM in humans has been interpreted within the predictive coding framework and associated with activity in the temporo-parietal junction (TPJ). However, the evolutionary origins of these human mindreading abilities have been challenged since the concept was coined. Here we identify a brain region in the Rhesus macaque that shares computational properties with the human TPJ. We revealed, using a non-linguistic task and functional magnetic resonance imaging, that activity in a region of the macaque middle superior temporal cortex was specifically modulated by the predictability of social interactions. As in human TPJ, this region could be distinguished from other temporal regions involved in face processing. Our result suggests the existence of a precursor for the theory of mind ability in the last common ancestor of human and old-world monkeys.

neuroscience↗

bioRxiv2020

Epithelial cell biomarkers are predictive of response to biologic agents in Crohn's disease

ObjectiveTherapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohns disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ), and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis with respect to response to VDZ. DesignIleal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST. In a 5-center academic retrospective cohort of CD patients, ileal MVL was analyzed to determine its predictive value for response to VDZ. Correlation between ileal MVL and IEC pyroptosis was determined, and the discriminant ability of the combination of two biomarkers to VDZ was examined. ResultsClinical response in UST was significantly higher than placebo (65% vs. 39%, p=0.03), with patients with normal MVL (>1.7 {micro}m) having the greatest therapeutic effect: 85% vs. 20% (p=0.02). For VDZ, clinical response with MVL of 1.35-1.55 {micro}m was 82% vs. 44% (<1.35 {micro}m) and 40% (>1.55 {micro}m) (p=0.038). There was no correlation between ileal MVL and IEC pyroptosis. The combination criteria of ileal pyroptosis < 14 positive cells/1000 IECs or MVL of 1.35-1.55 {micro}m could identify 84% of responders and 67% of non-responders (p=0.001). ConclusionsIleal MVL was predictive of response to UST and VDZ in prospective and retrospective CD cohorts. It was independent of ileal IEC pyroptosis, combination of the two biomarkers enhanced the discriminate ability of responders from non-responders to VDZ.

cell biology↗

bioRxiv2019

SOX9 is required for kidney fibrosis and regulates NAV3 to control renal myofibroblast function in mice and humans

Renal fibrosis is a common endpoint for many chronic kidney diseases. Extracellular matrix (ECM) from myofibroblasts causes progressive scarring and organ failure. The mechanisms underlying fibrogenesis and how it is sustained are incompletely understood. Here, we show that the transcription factor, Sex determining region Y-box 9 (SOX9), is required for kidney fibrosis. From genome-wide analysis we identify Neuron navigator 3 (NAV3) downstream of SOX9. NAV3 was upregulated in kidney disease in patients and following renal injury in mice colocalised with SOX9. By establishing an in vitro model of renal pericyte transition to myofibroblast we demonstrated that NAV3 is required for multiple aspects of fibrogenesis including actin polymerization linked to cell migration and sustaining SOX9 and active YAP1 levels. In summary, our work discovers novel SOX9-NAV3-YAP1/SOX9 circuitry as a new mechanism to explain the progression of kidney fibrosis and points to NAV3 as a novel target for pharmacological intervention.

cell biology↗