bims-raghud 2025-06-08 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–06–08
fourteen papers selected by
Irene Sambri, TIGEM

Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.
Autocrine TGF-β signaling promotes cell motility and chemokine secretion in an angiomyolipoma-derived cell model of lymphangioleiomyomatosis.
TSC2/mTORC1 integrates deoxynivalenol signals recognized by membrane receptors IR and EGFR to restrict intestinal stem cell function.
An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying SFPQ-TFE3 driven translocation RCC.
DEPDC5 regulates the strength of excitatory synaptic transmission by interacting with ubiquitin-specific protease 46.
Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling.
Dissociation of the mTOR protein interaction network following neuronal activation is altered by Shank3 mutation.
Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.
Enhancing human pluripotent stem cell differentiation to cardiomyocytes through cardiac progenitor reseeding and cryopreservation.
Inhibition of virally induced TFEB proteasomal degradation as a host-centric therapeutic approach for coronaviral infection.
The Effect of FPR2 on the Regulation of Trophoblast Autophagy via the PI3K/AKT/mTOR Signaling Pathway in Preeclampsia.
mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.
YAP/TAZ in the Nervous System: Key Regulatory and Therapeutic Implications in Neurological Disorders.
Exploring inflammatory and fibrotic mechanisms driving diabetic nephropathy progression.

Res Sq. 2025 May 13. pii: rs.3.rs-5073364. [Epub ahead of print]

Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.

Rachel Jansen, Clement Maghe, Karla Tapia, Selina Wu, Serim Yang, Xuefeng Ren, Roberto Zoncu, James Hurley.

Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome via the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine (Arg), the GTPase activating protein (GAP) complex, GATOR1, promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the Arg-sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic Arg, we determined the cryo-EM structure of GATOR2 bound to apo-CASTOR1. Two MIOS WD40 domain β-propellers of the GATOR2 cage engage with both subunits of a single CASTOR1 homodimer. Each propeller binds to a negatively charged MIOS-binding interface (MBI) on CASTOR1 that is distal to the Arg pocket. The structure shows how Arg-triggered loop ordering in CASTOR1 blocks the MBI, switches off its binding to GATOR2, and so activates mTORC1.

DOI: https://doi.org/10.21203/rs.3.rs-5073364/v1
Am J Pathol. 2025 May 30. pii: S0002-9440(25)00182-8. [Epub ahead of print]

Autocrine TGF-β signaling promotes cell motility and chemokine secretion in an angiomyolipoma-derived cell model of lymphangioleiomyomatosis.

Anna Moskal, Rafał Myrczek, Mateusz Wawro, Lara Ruiz Auladell, Alexandra Baiges, Irene Garcia, Francesca Mateo Gonzalez, Miquel Angel Pujana, Jakub Kochan, Alicja Hinz, Elżbieta Radzikowska, Sophie Lucas, Joanna Bereta, Renata Mezyk-Kopec.

Lymphangioleiomyomatosis (LAM) is a rare systemic disease that affects young women and is classified as a low-grade metastasizing neoplasm. It is characterized by uncontrolled proliferation of LAM cells within the lung parenchyma, which results from loss-of-function mutations in tuberous sclerosis complex 2 (TSC2) or 1 (TSC1) and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal cell growth leads to cyst formation and lung damage. Rapamycin-based therapy is the only approved treatment. Although it stabilizes the lung function in most patients, it has several limitations. Therefore, new therapeutic strategies are needed. This study examined the role of transforming growth factor β (TGF-β), a pleiotropic cytokine with well-established pro-tumorigenic activity, in LAM cell biology. Using a TSC2-deficient angiomyolipoma-derived cell line, it was found that TSC2-/- cells exhibited a higher expression of TGFβ1 and TGFβ3 than cells with restored TSC2 expression. Additionally, TSC2-/- cells expressed glycoprotein A repetitions predominant (GARP) and integrin β8, which promote TGF-β activation. Inhibition of TGF-β signaling in TSC2-/- cells reduced their migration in a wound healing assay, impaired transmigration through a 3D matrix, and decreased the expression of monocyte chemoattractant protein-1 (MCP-1). These findings provide new insights into the regulation of processes contributing to LAM progression and point to TGF-β as one of the potential targets for LAM treatment.

DOI: https://doi.org/10.1016/j.ajpath.2025.04.019
J Hazard Mater. 2025 May 29. pii: S0304-3894(25)01685-1. [Epub ahead of print]494 138769

TSC2/mTORC1 integrates deoxynivalenol signals recognized by membrane receptors IR and EGFR to restrict intestinal stem cell function.

Cai-Xia Dou, Hao-Zhan Qu, Ying-Chao Qin, Xiao-Fan Wang, Hui-Chao Yan, Run-Sheng Li, Yu-Guang Zhao, Jia-Yi Zhou, Xiu-Qi Wang.

  Deoxynivalenol (DON) is a chemically stable mycotoxin with a slow natural degradation rate. Consumption of DON-contaminated food and feed poses significant health risks to human and livestock, leading to reduced productivity and substantial economic losses. The functionality of intestinal stem cells (ISCs) are compromised following sustained intracellular deoxynivalenol (DON) stress. Yet, it remains unclear how membrane receptors integrate extracellular DON to impair orderly ISC fate commitments. Here, we found that mechanistic target of rapamycin complex 1 (mTORC1), as well as its upstream signaling pathways such as insulin, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase-Akt (PI3K/Akt), are involved in DON restraining ISC proliferation and differentiation to disrupt piglet jejunal epithelial structural integrity through single-cell RNA sequencing (scRNA-seq). Using the ex vivo porcine intestinal organoid and in vitro IPEC-J2 cell line, we identified that mTORC1 activation and tuberous sclerosis complex 2 (TSC2) knockout could repair DON-induced ISC injury. Furthermore, DON repressed the TSC2/mTORC1 upstream membrane receptors insulin receptor (IR) and epidermal growth factor receptor (EGFR); conversely, overexpression of IR or EGFR, especially co-overexpression of both, maintained the ISC regeneration in the presence of DON. Importantly, exothermic reactions between DON and the extracellular domains of IR/EGFR monitored by isothermal titration calorimetry (ITC) revealed a composite response consisting of DON recruitment and IR/EGFR conformational dynamics. Therefore, we have ascertained that the extracellular DON regulates intracellular TSC2/mTORC1 activity to restrict ISC function through the interaction with membrane receptors IR and EGFR.

Keywords:  Deoxynivalenol; Insulin and epidermal growth factor receptors; Intestinal stem cells; Piglets; TSC2/mTOR signaling

DOI:  https://doi.org/10.1016/j.jhazmat.2025.138769
iScience. 2025 Apr 18. 28(4): 112122

An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying SFPQ-TFE3 driven translocation RCC.

Maroussia M P Ganpat, Francisco Morales-Rodriguez, Nhung Pham, Philip Lijnzaad, Terezinha de Souza, Sepide Derakhshan, Arianna Fumagalli, Peter Zeller, Aleksandra Balwierz, Dilara Ayyildiz, Marry M van den Heuvel-Eibrink, Ronald R de Krijger, Alexander van Oudenaarden, Thanasis Margaritis, Susana M Chuva de Sousa Lopes, Jarno Drost.

  Translocation renal cell carcinoma (tRCC) is a rare, aggressive kidney cancer primarily occurring in children. They are genetically defined by translocations involving MiT/TFE gene family members TFE3 or TFEB. The biology underlying tRCC development remains poorly understood, partly due to the lack of representative experimental models. We utilized human kidney organoids, or tubuloids, to engineer a tRCC model by expressing one of the most common MiT/TFE fusions, SFPQ-TFE3. Fusion-expressing tubuloids adopt a tRCC-like phenotype and gene expression signature in vitro and grow as clear cell RCC upon xenotransplantation in mice. Genome-wide binding analysis suggests that SFPQ-TFE3 reprograms gene expression signatures by widespread, aberrant DNA binding. Combining these analyses with single-cell mRNA readouts reveals a derailed epithelial differentiation trajectory that is at the root of transformation toward tRCC. Our study demonstrates that SFPQ-TFE3 expression is sufficient to transform kidney epithelial cells into tRCC and defines the trajectories underlying malignant transformation.

Keywords:  Bioengineering; Natural sciences; biological sciences; tissue engineering

DOI:  https://doi.org/10.1016/j.isci.2025.112122
Neurobiol Dis. 2025 Jun 02. pii: S0969-9961(25)00201-3. [Epub ahead of print] 106985

DEPDC5 regulates the strength of excitatory synaptic transmission by interacting with ubiquitin-specific protease 46.

Maria Sabina Cerullo, Caterina Canevari, Antonella Marte, Alexandre Bacq, Antonio De Fusco, Marina Maletic, Stéphanie Baulac, Fabio Benfenati.

  DEP-domain containing-5 (DEPDC5) is part of the GATOR1 complex that inhibits the mechanistic target of rapamycin complex-1 (mTORC1). Loss-of-function mutations in human DEPDC5 are the most common cause of lesional or non-lesional focal epilepsies associated with mTOR hyperactivation. Depdc5 silencing in mature neurons leads to excitation/inhibition imbalance and increased excitatory synapse strength. However, no link exists between mTORC1 hyperactivity and the increased activity of glutamatergic synapses. Here, we found that genetic deletion of Depdc5 in a conditional knockout (cKO) mouse recapitulates the excitatory/inhibitory imbalance observed after transient Depdc5 silencing, with increased strength of excitatory transmission and unaffected inhibitory transmission. In Depdc5 cKO neurons, the increased glutamate quantal size and response to exogenous glutamate are attributable to a higher density of GluA1-containing AMPA glutamate receptors due to a shift of the GluA1 subunit from the intracellular pool to the plasma membrane. The DEPDC5 protein interaction network included WDR48, WDR20, and USP46, a ubiquitin-specific protease that regulates GluA1, as key binding partners, along with previously established components of the mTORC1 signaling pathway. In the absence of DEPDC5, USP46 levels increase, and ubiquitination of GluA1 decreases accordingly. Either knockdown of USP46 or rapamycin treatment rescues both the increased glutamate quantal size and USP46 increase caused by Depdc5 deletion, indicating that USP46 overexpression depends on mTORC1 hyperactivity. The data indicate that the DEPDC5/mTORC1 system physiologically controls the excitatory strength by negatively modulating USP46 activity and AMPA receptor deubiquitination, and that failure of this effect can contribute to the development of the Depdc5-linked epileptic phenotype.

Keywords:  AMPA receptors; DEPDC5 interactome; Depdc5 mutations; Deubiquitination; Excitatory synaptic strength; Primary neurons

DOI:  https://doi.org/10.1016/j.nbd.2025.106985
Sci Rep. 2025 Jun 04. 15(1): 19652

Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling.

Eike Schwartze, Eva Pfister, Nicole Endlich, Tim Endlich, Kerstin Amann, Maike Büttner-Herold, Jeff Pippin, Stuart J Shankland, Christoph Daniel.

  Focal segmental glomerular sclerosis (FSGS) is considered an irreversible lesion in kidney disease. Here, we investigated the role of the wnt4/β-Catenin signaling pathway in FSGS lesion formation and the crosstalk between PECs and podocytes in a transgenic FSGS rat model and human primary FSGS to explore potential sex-specific differences and therapeutic options. After model induction in rats, we observed strong podocytes loss on day 7, which was significantly higher in male than in female rats. Starting at d14, both glomerular mRNA and protein expression of Wnt4 were increased, but more pronounced in males. Wnt4 was localized to podocytes and β-Catenin to Pax8-positive lesions. The Wnt4 target gene CD44 was strongly upregulated on d7 and increased until the end of the experiment (d42). In cell culture, we confirmed that injured podocytes expressed and secreted Wnt4, which stimulated the expression of the Wnt target gene Axin2 in PECs but not in podocytes. Wnt4/β-Catenin pathway activation was confirmed in human biopsies with podocytopathic FSGS. In conclusion, the canonical Wnt/β-Catenin axis plays a critical role in the crosstalk between PECs and injured podocytes. Furthermore, sex-specific differences in podocyte injury and regeneration appear to be, at least in part, Wnt4-mediated.

Keywords:  Crosstalk; Injury; Parietal epithelial cell; Podocyte; Wnt-pathway

DOI:  https://doi.org/10.1038/s41598-025-04092-3
bioRxiv. 2025 May 23. pii: 2025.05.20.655155. [Epub ahead of print]

Dissociation of the mTOR protein interaction network following neuronal activation is altered by Shank3 mutation.

Devin T Wehle, Emily A Brown, Vera Stamenkovic, Felicia Harsh, Stephen E P Smith.

The mechanistic target of Rapamycin (mTOR) kinase pathway plays critical roles in neuronal function and synaptic plasticity, and its dysfunction is implicated in numerous neurological and psychiatric disorders. Traditional linear models depict mTOR signaling as a sequential phosphorylation cascade, but accumulating evidence supports a model that includes signaling through dynamic protein-protein interaction networks. To examine how neuronal mTOR signaling discriminates between distinct stimuli, we quantified phosphorylation events and protein co-association networks in primary mouse cortical neurons. Unexpectedly, neuronal mTOR activation by IGF or glutamate triggered dissociation-rather than the anticipated assembly-of protein complexes involving mTOR complex1 (TORC1), mTOR complex 2 (TORC2), and translational machinery, distinguishing neurons from proliferative cells. Applying in vitro homeostatic scaling paradigms revealed distinct combinatorial encoding of synaptic scaling direction: both up- and down-scaling induced dissociation of translational complexes, but downscaling uniquely included dissociation of upstream pathway regulators. Cortical neurons from Shank3B knockout mice, modeling autism-associated Phelan-McDermid Syndrome, displayed baseline hyperactivation of the mTOR network, which reduced the dynamic range of network responses to homeostatic scaling and pharmacological inhibition. These findings reveal that neuronal mTOR signaling employs stimulus-specific combinations of dissociative protein interaction modules to encode opposing forms of synaptic plasticity.

DOI: https://doi.org/10.1101/2025.05.20.655155
Nat Commun. 2025 Jun 05. 16(1): 5209

Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.

Ran Chen, Bin Liu, Dawid Jaślan, Lucija Kucej, Veronika Kudrina, Belinda Warnke, Yvonne E Klingl, Arnas Petrauskas, Sandra Prat Castro, Kenji Maeda, Christian Grimm, Marja Jäättelä.

The proper function of lysosomes depends on their ability to store and release calcium. While several lysosomal calcium release channels have been described, how lysosomes replenish their calcium stores in placental mammals has not been determined. Using genetic depletion and overexpression techniques combined with electrophysiology and visualization of subcellular ion concentrations and their fluxes across the lysosomal membrane, we show here that TMEM165 imports calcium to the lysosomal lumen and mediates calcium-induced lysosomal proton leakage. Accordingly, TMEM165 accelerates the recovery of cells from cytosolic calcium overload thereby enhancing cell survival while causing a significant acidification of the cytosol. These data indicate that in addition to its previously identified role in the glycosylation of proteins and lipids in the Golgi, a fraction of TMEM165 localizes on the lysosomal limiting membrane, where its putative calcium/proton antiporter activity plays an essential role in the regulation of intracellular ion homeostasis and cell survival.

DOI: https://doi.org/10.1038/s41467-025-60349-5
iScience. 2025 May 16. 28(5): 112452

Enhancing human pluripotent stem cell differentiation to cardiomyocytes through cardiac progenitor reseeding and cryopreservation.

Austin K Feeney, Aaron D Simmons, Claire J Peplinski, Xiaotian Zhang, Sean P Palecek.

  Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have the potential to transform the understanding of heart development and heart failure treatment. However, hPSC-CM differentiation efficiency is plagued by batch-to-batch and line-to-line variability. Here, we describe a method to improve CM purity by 10-20% (absolute) without negatively affecting contractility, sarcomere structure, multinucleation, junctional Cx43, or CM number by detaching and reseeding progenitors between the EOMES+ mesoderm and ISL1+/NKX2-5+ cardiac progenitor stages. Moreover, we demonstrate that EOMES+ mesoderm and ISL1+/NKX2-5+ cardiac progenitors are cryopreservable with similar improvements in CM purity after resuming differentiation, facilitating storage of large batches of hPSC-CM progenitors for on-demand CM production. Reseeding during differentiation also enables transition to defined extracellular matrices, including fibronectin, vitronectin, and laminin-111, which all supported hPSC-derived EOMES+ mesoderm and ISL1+/NKX2-5+ cardiac progenitor differentiation to CMs. In summary, we present a method to increase hPSC-CM differentiation purity and demonstrate that specific CM progenitors are amenable to cryopreservation.

Keywords:  Biological sciences; Biological sciences research methodologies; Technical aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.112452
Sci Adv. 2025 Jun 06. 11(23): eadv4033

Inhibition of virally induced TFEB proteasomal degradation as a host-centric therapeutic approach for coronaviral infection.

Travis B Lear, Mads B Larsen, Bo Lin, Benjamin R Treat, Qing Cao, Áine N Boudreau, Karina C Lockwood, Irene Alfaras, Jason R Kennerdell, Laura Salminen, Daniel P Camarco, Yao Tong, Jing Ma, Jie Liu, Jay X Tan, Ferhan Tuncer, John J Villandre, Lucas Hertzel, Michael M Myerburg, Yanwen Chen, Claudette St Croix, Yusuke Sekine, John W Evankovich, Simon M Barratt-Boyes, Toren Finkel, Bill B Chen, Yuan Liu.

The endolysosomal pathway plays an evolutionarily conserved role in pathogen clearance, and viruses have evolved complex mechanisms to evade this host defense system. Here, we describe a previously unidentified aspect of coronaviral infection, whereby the master transcriptional activator of lysosomal homeostasis-TFEB-is targeted for proteasomal-mediated degradation upon viral infection. Through mass spectrometry analysis and an unbiased small interfering RNA screen, we identify that TFEB protein stability is coordinately regulated by the E3 ubiquitin ligase subunit DCAF7 and the PAK2 kinase. We derive a series of novel small molecules that interfere with the DCAF7-TFEB interaction. These agents inhibit virus-induced TFEB degradation and demonstrate broad antiviral activities including attenuating severe acute respiratory syndrome coronavirus 2 infection in two animal models. Together, these results delineate a virally triggered pathway that impairs lysosomal homeostasis in the host. Small molecule E3 ubiquitin ligase DCAF7 inhibitors that restore lysosomal function represent a novel class of host-directed, antiviral therapies useful for current and potentially future coronaviral variants.

DOI: https://doi.org/10.1126/sciadv.adv4033
FASEB J. 2025 Jun 15. 39(11): e70697

The Effect of FPR2 on the Regulation of Trophoblast Autophagy via the PI3K/AKT/mTOR Signaling Pathway in Preeclampsia.

Ning Jiang, Meijuan Zhou, Yingying Le, Li Xiao, Changqing Zhang, Shuxian Li, Junjun Guo, Yue Wu, Meihua Zhang, Xietong Wang.

  Preeclampsia (PE) is associated with significant maternal and fetal morbidity and mortality, with placental trophoblast dysfunction playing a central role in its pathogenesis. Autophagic imbalance impacts trophoblast function, and the regulatory role of formyl-peptide receptor 2 (FPR2) in trophoblast autophagy and placental function requires further investigation. We used the HTR8/SVneo cell line and Fpr2 knockout mice to explore the role of FPR2 in trophoblast function. The expression of FPR2 and autophagy levels were elevated in PE patients and models. FPR2 knockdown reversed the H2O2-induced inhibition of trophoblast function and downregulated autophagy-related proteins. H2O2 activated the PI3K/AKT/mTOR pathway, but this activation was reduced by FPR2 knockdown or 3-MA pretreatment. We demonstrate that FPR2 regulates trophoblast autophagy through the PI3K/AKT/mTOR signaling pathway, contributing to the development of PE. These findings may offer new insights into the prevention and treatment of PE.

Keywords:  FPR2; HTR8/SVneo cells; PI3K/AKT/mTOR; autophagy; preeclampsia (PE)

DOI:  https://doi.org/10.1096/fj.202402938RR
Cell Commun Signal. 2025 May 31. 23(1): 256

mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.

Hugo E Verdejo, Valentina Parra, Andrea Del Campo, Cesar Vasquez-Trincado, Damian Gatica, Camila Lopez-Crisosto, Jovan Kuzmicic, Leslye Venegas-Zamora, Ursula Zuñiga-Cuevas, Mayarling F Troncoso, Rodrigo Troncoso, Beverly A Rothermel, Mario Chiong, E Dale Abel, Sergio Lavandero.

   INTRODUCTION: Cardiac mitochondrial function is intricately regulated by various processes, ultimately impacting metabolic performance. Additionally, protein turnover is crucial for sustained metabolic homeostasis in cardiomyocytes.
OBJECTIVE: Here, we studied the role of mTOR in OPA-1 cleavage and its consequent effects on mitochondrial dynamics and energetics in cardiomyocytes.
RESULTS: Cultured rat cardiomyocytes treated with rapamycin for 6-24 h showed a significant reduction in phosphorylation of p70S6K, indicative of sustained inhibition of mTOR. Structural and functional analysis revealed increased mitochondrial fragmentation and impaired bioenergetics characterized by decreases in ROS production, oxygen consumption, and cellular ATP. Depletion of either the mitochondrial protease OMA1 or the mTOR regulator TSC2 by siRNA, coupled with an inducible, cardiomyocyte-specific knockout of mTOR in vivo, suggested that inhibition of mTOR promotes mitochondrial fragmentation through a mechanism involving OMA1 processing of OPA-1. Under homeostatic conditions, OMA1 activity is kept under check through an interaction with microdomains in the inner mitochondrial membrane that requires prohibitin proteins (PHB). Loss of these microdomains releases OMA1 to cleave its substrates. We found that rapamycin both increased ubiquitination of PHB1 and decreased its abundance, suggesting proteasomal degradation. Consistent with this, the proteasome inhibitor MG-132 maintained OPA-1 content in rapamycin-treated cardiomyocytes. Using pharmacological activation and inhibition of AMPK our data supports the hypothesis that this mTOR-PHB1-OMA-OPA-1 pathway impacts mitochondrial morphology under stress conditions, where it mediates dynamic changes in metabolic status.
CONCLUSIONS: These data suggest that mTOR inhibition disrupts mitochondrial integrity in cardiomyocytes by promoting the degradation of prohibitins and OPA-1, leading to mitochondrial fragmentation and metabolic dysfunction, particularly under conditions of metabolic stress.

Keywords:  AMPK; Mitochondrial fusion; OMA1; OPA-1; Prohibitin; Rapamycin; mTOR

DOI:  https://doi.org/10.1186/s12964-025-02240-w
Behav Brain Res. 2025 Jun 03. pii: S0166-4328(25)00258-X. [Epub ahead of print] 115672

YAP/TAZ in the Nervous System: Key Regulatory and Therapeutic Implications in Neurological Disorders.

Jia-Xin Luo, Dong-Mei Wang, Zhao Ran, Mei-Hong Lu.

  In recent years, an increasing number of studies have highlighted YAP/TAZ, the downstream effectors of the Hippo pathway, as promising therapeutic targets for various neurological diseases. Although YAP/TAZ signaling pathway involves multiple complex cascades of signal transduction, their specific functions across various cell types and microenvironments remain inadequately understood. Particularly in the nervous system, our comprehension of how YAP/TAZ regulates the physiological activities of diverse neural cell types, and thereby influences the onset and progression of neurological diseases, is still limited. This review investigates YAP/TAZ's function and regulation, summarizing evidence that linking them to essential regulatory processes within the nervous system. It analyzes their roles across various neuronal cell types and explores their interactions with multiple signaling pathways. Furthermore, the review details the involvement of YAP/TAZ in a range of neurological disorders, emphasizing their potential as crucial mediators in these conditions. These insights point to potential therapeutic strategies that target YAP/TAZ for the treatment of neurological diseases.

Keywords:  Hippo Pathway; Neurological disorders; Signaling pathways crosstalk; Therapeutic Target; YAP/TAZ

DOI:  https://doi.org/10.1016/j.bbr.2025.115672
Cytokine Growth Factor Rev. 2025 May 29. pii: S1359-6101(25)00053-X. [Epub ahead of print]

Exploring inflammatory and fibrotic mechanisms driving diabetic nephropathy progression.

Zeeshan Ansari, Ayush Chaurasia, Neha, Nisha Sharma, Rakesh Kumar Bachheti, Prakash Chandra Gupta.

  Diabetic nephropathy (DN) remains a leading cause of end-stage renal disease, with inflammation and fibrosis serving as pivotal drivers of disease progression. Chronic hyperglycemia induces oxidative stress, activates immune pathways, and promotes extracellular matrix (ECM) accumulation, leading to irreversible kidney damage. Inflammatory cytokines contribute to DN progression, such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-6, and IL-17. Moreover, chemokines, their receptors, and adhesion molecules are critically involved in the progression of inflammation during the development of DN. On the other hand, several renal cell types contribute to the fibrotic process of DN by either producing ECM components directly or secreting profibrotic mediators that stimulate fibroblast activation. Fibroblasts, immune cells, and endothelial cells play pivotal roles in mediating fibrosis. Emerging evidence highlights the critical role of inflammatory and fibrotic signaling pathways in DN progression. The activation of the NF-κB, JAK-STAT, and NLRP3 inflammasome pathways contributes to sustained inflammation by promoting proinflammatory cytokine release and immune cell infiltration. Simultaneously, the TGF-β/Smad, Wnt/β-catenin, PI3K/Akt, and MAPK signaling pathways drive fibrosis by inducing ECM deposition and epithelialmesenchymal transition (EMT). Understanding these interconnected pathways provides insights into potential therapeutic targets for mitigating DN progression. In this review, we explore the molecular mechanisms that link inflammation and fibrotic responses to the progression of DN, focusing on signaling pathways, cellular mediators and therapeutic targets.

Keywords:  Chemokine; Cytokine; Diabetic kidney disease; MAPK; NF-κB; Renal fibrosis; TGF-β

DOI:  https://doi.org/10.1016/j.cytogfr.2025.05.007