bims-raghud 2025-04-27 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–04–27
eleven papers selected by
Irene Sambri, TIGEM

SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.
Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1.
Human kidney organoids for modeling the development of different diseases.
Autosomal dominant polycystic kidney disease: an overview of recent genetic and clinical advances.
The hippo pathway: a molecular bridge between environmental cues and pace of life.
Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.
iPSC-derived and Patient-Derived Organoids: Applications and challenges in scalability and reproducibility as pre-clinical models.
High throughput screening assay for the identification of ATF4 and TFEB activating compounds.
D-mannose suppresses the angiogenesis and progression of colorectal cancer.
MicroRNA in cancer therapy: breakthroughs and challenges in early clinical applications.
Modeling heart failure by induced pluripotent stem cell-derived organoids.

Autophagy. 2025 Apr 25. 1-3

SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.

Mingzhu Tang, Guang Lu, Han-Ming Shen.

  Mitophagy, selective degradation of dysfunctional mitochondria by the autophagy-lysosome pathway, is critical for maintaining cellular homeostasis. In recent years, significant progress has been made in understanding how PINK1 (PTEN-induced kinase 1)-mediated phosphorylation and the E3 ubiquitin (Ub) ligase (PRKN/parkin)-mediated ubiquitination form a positive feedforward loop in control of mitophagy. Nevertheless, a fundamental question remains: How is PINK1 transcriptionally modulated under mitochondrial stress to finely support mitophagy? Recently, we unveiled a novel mechanism in control of PINK1 transcription by SMAD3 (SMAD family member 3), an essential component of the TGFB/TGFβ (transforming growth factor beta)-SMAD signaling pathway. Upon mitochondrial depolarization, SMAD3 is activated through PINK1-mediated phosphorylation of SMAD3 at serine 423/425 independent of canonical TGFB signaling. More importantly, the SMAD3-PINK1 regulatory axis appears to functionally provide a pro-survival mechanism against mitochondrial stress. Therefore, PINK1 and SMAD3 constitute a newly discovered positive feedforward loop to regulate mitophagy, highlighting the need for further exploring the crosstalk between TGFB-SMAD signaling and mitophagy.

Keywords:  Mitophagy; PINK1; SMAD3; phosphorylation; transcription

DOI:  https://doi.org/10.1080/15548627.2025.2496364
Cell Res. 2025 Apr 21.

Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1.

Xiaobo He, Qiu-Xia Wang, Denghui Wei, Yujie Lin, Xia Zhang, Yuanzhong Wu, Xuexia Qian, Zhihao Lin, Beibei Xiao, Qinxue Wu, Zhen Wang, Fengtao Zhou, Zhihao Wei, Jingxuan Wang, Run Gong, Ruhua Zhang, Qingling Zhang, Ke Ding, Song Gao, Tiebang Kang.

Oncogenic mutations in EGFR often result in EGF-independent constitutive activation and aberrant trafficking and are associated with several human malignancies, including non-small cell lung cancer. A major consequence of EGFR mutations is the activation of the mechanistic target of rapamycin complex 1 (mTORC1), which requires EGFR kinase activity and downstream PI3K/AKT signaling, resulting in increased cell proliferation. However, recent studies have elucidated kinase-independent roles of EGFR in cell survival and cancer progression. Here, we report a cis mTORC1 activation function of EGFR that is independent of its kinase activity. Our results reveal that lysosomal localization of EGFR is critical to mTORC1 activation, where EGFR physically binds Rheb, acting as a guanine exchange factor (GEF) for Rheb, with its Glu804 serving as a potential glutamic finger. Genetic knock-in of EGFR-E804K in cells reduces the level of GTP-bound Rheb, and significantly suppresses mTORC1 activation, cell proliferation and tumor growth. Different tyrosine kinase inhibitors exhibit distinct effects on EGFR-induced mTORC1 activation, with afatinib, which additionally blocks EGFR's GEF activity, causing a much greater suppression of mTORC1 activation and cell growth, and erlotinib, which targets only kinase activity, resulting in only a slight decrease. Moreover, a novel small molecule, BIEGi-1, was designed to target both the Rheb-GEF and kinase activities of EGFR, and shows a strong inhibitory effect on the viability of cells harboring EGFR mutants. These findings unveil a fundamental event in cell growth and suggest a promising strategy against cancers with EGFR mutations.

DOI: https://doi.org/10.1038/s41422-025-01110-x
Curr Top Dev Biol. 2025 ;pii: S0070-2153(24)00123-6. [Epub ahead of print]163 364-393

Human kidney organoids for modeling the development of different diseases.

Elena Ceccotti, Armina Semnani, Benedetta Bussolati, Stefania Bruno.

  The increasing incidence of kidney diseases has highlighted the need for in vitro experimental models to mimic disease development and to test new therapeutic approaches. Traditional two-dimensional in vitro experimental models are not fully able to recapitulate renal diseases. Instead, kidney organoids represent three-dimensional models that better mimic the human organ from both structural and functional points of view. Human pluripotent stem cells (PSCs), both embryonic and induced, are ideal sources for generating renal organoids. These organoids contain all renal cell types and the protocols to differentiate PSCs into renal organoids consist of three different stages that recapitulate embryonic development: mesodermal induction, nephron progenitor formation, and nephron differentiation. Recently it has been establish a renal organoid model where collecting ducts are also present. In this case, the presence of ureteric bud progenitor cells is essential. Renal organoids are particularly useful for studying genetic diseases, by introducing the specific mutations in PSCs by genome editing or generating organoids from patient-derived PSCs. Moreover, renal organoids represent promising models in toxicology studies and testing new therapeutic approaches. Renal organoids can be established also from adult stem cells. This type of organoid, named tubuloid, is composed only of epithelial cells and recapitulates the tissue repair process. The tubuloids can be generated from adult stem or progenitor cells, obtained from renal biopsies or urine, and are promising in vitro models for studying tubular functions, diseases, and regeneration. Tubuloids can be derived from patients and permit the study of genetic diseases, performing personalized drug screening and modeling renal pathologies.

Keywords:  Adult stem cells; Disease modeling; Drug screening; Embryonic stem cells; Human pluripotent stem cells; Induced stem cells; Personalized medicine; Tubuloids

DOI:  https://doi.org/10.1016/bs.ctdb.2024.12.001
Ren Fail. 2025 Dec;47(1): 2492374

Autosomal dominant polycystic kidney disease: an overview of recent genetic and clinical advances.

Abdul Hamid Borghol, Marie Therese Bou Antoun, Christian Hanna, Mahdi Salih, Frederic F Rahbari-Oskoui, Fouad T Chebib.

  Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disease, characterized by the progressive development of multiple kidney cysts, leading to a gradual decline in kidney function. ADPKD is also the fourth leading cause of kidney failure (KF) in adults. In addition to kidney manifestations, ADPKD is associated with various extrarenal features, including liver cysts, cardiovascular abnormalities, intracranial aneurysms, and chronic pain with significant impact on patients' quality of life. While several disease-modifying agents have been tested in ADPKD, tolvaptan remains the only approved drug by the US Food and Drug Administration. The Mayo Imaging Classification is currently the most practical tool for predicting rate of kidney disease progression in ADPKD. This review provides a comprehensive overview of ADPKD, focusing on its genetics, pathophysiology, clinical presentation, management, and prognostic tools. Advances in diagnostic imaging and genetic testing have improved the early detection of ADPKD, allowing better classification of patients and prediction of KF. The review also discusses current therapeutic approaches to ADPKD, including tolvaptan, a vasopressin V2-receptor antagonist. Additionally, we address specific issues in children and pregnant individuals with ADPKD. Despite substantial progress in understanding ADPKD, there is a large need for additional effective treatments and prognostic markers to provide a more personalized care for these patients.

Keywords:  ADPKD; Polycystic liver disease; polycystic kidney disease; tolvaptan; total kidney volume

DOI:  https://doi.org/10.1080/0886022X.2025.2492374
BMC Ecol Evol. 2025 Apr 24. 25(1): 35

The hippo pathway: a molecular bridge between environmental cues and pace of life.

Ehsan Pashay Ahi, Bineet Panda, Craig R Primmer.

The pace of life (POL) is shaped by a complex interplay between genetic and environmental factors, influencing growth, maturation, and lifespan across species. The Hippo signaling pathway, a key regulator of organ size and cellular homeostasis, has emerged as a central integrator of environmental cues that modulate POL traits. In this review, we explore how the Hippo pathway links environmental factors-such as temperature fluctuations and dietary energy availability-to molecular mechanisms governing metabolic balance, hormonal signaling, and reproductive timing. Specifically, we highlight the regulatory interactions between the Hippo pathway and metabolic sensors (AMPK, mTOR, SIRT1 and DLK1-Notch), as well as hormonal signals (IGF-1, kisspeptin, leptin, cortisol, thyroid and sex steroids), which together orchestrate key life-history traits, including growth rates, lifespan and sexual maturation, with a particular emphasis on their role in reproductive timing. Furthermore, we consider its role as a potential coordinator of POL-related molecular processes, such as telomere dynamics and epigenetic mechanisms, within a broader regulatory network. By integrating insights from molecular biology and eco-evolutionary perspectives, we propose future directions to dissect the Hippo pathway's role in POL regulation across taxa. Understanding these interactions will provide new perspectives on how organisms adaptively adjust life-history strategies in response to environmental variability.

DOI: https://doi.org/10.1186/s12862-025-02378-8
EMBO Mol Med. 2025 Apr 22.

Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.

Sara Clerici, Alessandra Boletta.

  Primary cilia are solitary organelles formed by a microtubule-based skeleton protruding in a single copy on the surface of most cells. Alterations in their function cause a plethora of human conditions collectively called the ciliopathies. The kidney is frequently and severely affected in the ciliopathies, presenting with a spectrum of phenotypes. Cyst formation is a common trait of all renal ciliopathies. Besides this common manifestation, however, the renal ciliopathies present with profoundly different phenotypes, resulting in either polycystic kidney disease (PKD) or nephronophthisis (NPH) phenotypes. The past decade has seen a surge of studies highlighting metabolic reprogramming as a major feature of PKD, with a distinct involvement of mitochondrial dysfunction. This discovery has brought forward the development of novel therapeutic approaches. More recent evidence suggests that primary cilia modulate the mitochondrial production of energy in response to environmental cues. Here, we summarize the evidence available to date and propose a more general involvement of metabolic and mitochondrial alterations in the renal ciliopathies that might in principle help defining the profoundly different, and potentially opposite, manifestations observed.

Keywords:  Cilia; Ciliopathies; Kidney Cysts; Metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44321-025-00239-x
Curr Res Toxicol. 2024 ;7 100197

iPSC-derived and Patient-Derived Organoids: Applications and challenges in scalability and reproducibility as pre-clinical models.

Elisa Heinzelmann, Francesco Piraino, Mariana Costa, Aline Roch, Maxim Norkin, Virginie Garnier, Krisztian Homicsko, Nathalie Brandenberg.

  Recent advancements in stem cell technology have led to the development of organoids - three-dimensional (3D) cell cultures that closely mimic the structural and functional characteristics of human organs. These organoids represent a significant improvement over traditional two-dimensional (2D) cell cultures by preserving native tissue architecture and cellular interactions critical for physiological relevance. This review provides a comprehensive comparison between two main types of organoids: induced Pluripotent Stem Cell (iPSC)-derived and Adult Stem Cell (ASC)-derived (also known as Patient-Derived Organoids, PDOs). iPSC-derived organoids, derived from reprogrammed cells, exhibit remarkable plasticity, and can model a wide range of tissues and developmental stages. They are particularly valuable for studying early human development, genetic disorders, and complex diseases. However, challenges such as prolonged differentiation protocols and variability in maturation levels remain significant hurdles. In contrast, ASC-derived organoids, generated directly from patient tissues, faithfully recapitulate tissue-specific characteristics and disease phenotypes. This fidelity makes them indispensable for personalized medicine applications, including drug screening, disease modeling, and understanding individualized treatment responses. The review highlights the unique advantages and limitations of each organoid type, emphasizing their roles in advancing biomedical research and drug discovery. It addresses key challenges in organoid technology, such as scalability, reproducibility, and the need for standardized culture protocols. Furthermore, it explores recent innovations in scaffold-guided organoid engineering and the integration of organoids with advanced technologies like artificial intelligence and high-throughput screening. The integration of organoids with cutting-edge technologies holds promise for enhancing their utility in modeling complex human diseases and accelerating drug discovery and development. By providing more physiologically relevant models of human organs, organoid technology is poised to revolutionize biomedical research, offering new insights into disease mechanisms and personalized therapeutic strategies.

Keywords:  3D cell culture; Induced Pluripotent Stem Cells (iPSCs); Micro Physiological Systems (MPS); Organoids; Patient-Derived Organoids (PDOs); Pre-clinical models

DOI:  https://doi.org/10.1016/j.crtox.2024.100197
Autophagy Rep. 2025 ;pii: 2473765. [Epub ahead of print]4(1):

High throughput screening assay for the identification of ATF4 and TFEB activating compounds.

Daniel J Pfau, Ruslana Bryk.

  Macrophages act to defend against infection, but can fail to completely prevent bacterial replication and dissemination in an immunocompetent host. Recent studies have shown that activation of a host transcription factor, TFEB, a regulator of lysosomal biogenesis, could restrict intramacrophage replication of the human pathogen Mycobacterium tuberculosis and synergize with suboptimal levels of the antibiotic rifampin to reduce bacterial loads. Currently available small molecule TFEB activators lack selectivity and potency, but could be potentially useful in a variety of pathological conditions with suboptimal lysosomal activity. TFEB nuclear translocation and activation depend on its phosphorylation status which is controlled by multiple cellular pathways. We devised a whole cell, high throughput screening assay to identify small molecules that activate TFEB by establishing a stably transfected HEK293T reporter cell line for ATF4, a basic leucine zipper transcription factor induced by stress response and activated in parallel to TFEB. We optimized its use in vitro using compounds that target endoplasmic reticulum stress and intracellular calcium signaling. We report results from screening the commercially available LOPAC library and the Selleck Chemicals library modified to include only FDA-approved drugs and clinical research compounds. We identified twenty-one compounds across six clinical use categories that activate ATF4, and confirmed that two proteasome inhibitors promote TFEB activation. The results of this study provide an assay that could be used to screen for small molecules that activate ATF4 and TFEB and a potential list of compounds identified as activators of the ATF4 transcription factor in response to cellular stress.

Keywords:  host-directed therapy; macrophage; mycobacteria; stress response; tuberculosis

DOI:  https://doi.org/10.1080/27694127.2025.2473765
Acta Biochim Biophys Sin (Shanghai). 2025 Apr 21.

D-mannose suppresses the angiogenesis and progression of colorectal cancer.

Yu Du, Xinchao Zhang, Yixin Xu, Yuefan Zhou, Yanping Xu.

  Angiogenesis is an important factor influencing the development of solid tumors, and vascular endothelial growth factor receptor-2 (VEGFR2) is a central regulator of angiogenesis. Antibodies and inhibitors against VEGFR2 have been widely used in various malignancies. However, the regulatory mechanism of VEGFR2 has not been fully clarified. Here, we show that D-mannose can significantly inhibit angiogenesis and tumor growth by degrading VEGFR2. Specifically, D-mannose inactivates GSK3β by promoting the phosphorylation of GSK3β at Ser9, enhances the nuclear translocation of TFE3, and promotes lysosomal biogenesis, thereby increasing the lysosome-mediated degradation of VEGFR2. Thus, D-mannose significantly inhibits the proliferation, migration, and capillary formation of human umbilical vein endothelial cells (HUVECs) in vitro. Oral administration of D-mannose dramatically inhibits angiogenesis and tumor growth in mice. Our findings reveal a previously unrecognized anti-tumor mechanism of D-mannose by destabilizing VEGFR2 and provide a new strategy for the clinical treatment of colorectal cancer (CRC).

Keywords:  CRC; D-mannose; GSK3β; TFE3; VEGFR2; lysosome

DOI:  https://doi.org/10.3724/abbs.2025043
J Exp Clin Cancer Res. 2025 Apr 21. 44(1): 126

MicroRNA in cancer therapy: breakthroughs and challenges in early clinical applications.

Maria Teresa Di Martino, Pierosandro Tagliaferri, Pierfrancesco Tassone.

  MicroRNAs (miRNAs) have emerged as pivotal regulators in cancer biology, influencing tumorigenesis, progression, and resistance to therapy. Their ability to modulate multiple oncogenic and tumor-suppressive pathways positions them as promising therapeutic tools or targets. This review examines the dual role of miRNAs in solid and hematological malignancies, starting from their dysregulation in various cancer types. Therapeutic approaches, including miRNA replacement and inhibition strategies, are discussed alongside innovative delivery systems such as lipid nanoparticles and exosomes. Despite their transformative potential, challenges persist, including off-target effects, immune activation, and delivery inefficiencies. Recent clinical trials demonstrate both progress and hurdles, underscoring the need for advanced strategies to optimize specificity and minimize toxicity. This review provides an updated comprehensive overview of the current landscape of miRNA-based therapies under early clinical investigation and explores future directions for integrating these approaches into precision oncology.

Keywords:  Clinical trials; Early clinical trials; First-in-human; LNA; Locked nucleic acid; Non-coding RNA; Phase 1; miRNA; miRNA inhibitor; miRNA therapeutics; microRNA; ncRNA

DOI:  https://doi.org/10.1186/s13046-025-03391-x
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 18. pii: S0925-4439(25)00209-1. [Epub ahead of print]1871(6): 167861

Modeling heart failure by induced pluripotent stem cell-derived organoids.

Irene Bissoli, Francesco Alabiso, Cristina Cosentino, Aleksandra Seragnoli Chystyakova, Fabrizio Ferré, Francesco Alviano, Pasquale Marrazzo, Carla Pignatti, Giulio Agnetti, Romano Regazzi, Flavio Flamigni, Stefania D'Adamo, Silvia Cetrullo.

  Cardiac organoids offer significant advantages for in vitro studies, as their 3D structure and cellular composition more closely replicate tissue complexity compared to 2D models. This is particularly relevant for studying complex diseases like heart failure (HF), which involve multiple cell types and cardiac structures. Thus, the primary aim of this study was to produce self-assembled, scaffold-free cardiac organoids from induced pluripotent stem cells (iPSCs), capable of simulating key aspects of HF in vitro. Gene expression analysis confirmed a transition from stemness markers (OCT4, NANOG) to cardiac markers (TNNT2, DES), validating their cardiac phenotype. To induce hallmark HF features, endothelin-1 (ET-1) treatment was applied. Key findings indicate that this experimental model successfully reproduced HF pathological markers, including the upregulation of genes encoding atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and the cytoskeletal protein α-skeletal actin (ACTA1), along with changes in microRNA (miR) expression profiles. Functionally, ET-1 treatment reduced organoid contractility, indicating a decline in contractile function-a hallmark of HF. Furthermore, histological analyses by Thioflavin T (ThT) staining, ThT fluorescence assay and filter trap assay on protein extracts demonstrated protein aggregation following ET-1 treatment. Co-administration of various nutraceuticals was shown to mitigate these effects. These findings underscore the value of this ET-1-stimulated cardiac organoid model as a powerful platform for studying HF mechanisms and evaluating novel therapeutic approaches.

Keywords:  Endothelin-1; Heart failure; Induced pluripotent stem cells; Protein misfolding; microRNAs

DOI:  https://doi.org/10.1016/j.bbadis.2025.167861