bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–07–06
seven papers selected by
Irene Sambri, TIGEM
  1. A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model.
  2. Kidney organoids demonstrate that PTH1R drives a cystogenic cAMP-pPKA-pCREB axis in developmental Polycystic Kidney Disease.
  3. Transcription factor EB improves hypoxic pulmonary hypertension in fetal rats by suppressing NLRP3 inflammasome activation via induction of mitophagy.
  4. Differential Diagnosis and a Novel Mutation in Birt-Hogg-Dubé Syndrome: Insights from 2 Cases.
  5. Targeting the Hippo pathway in cancer.
  6. A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
  7. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  1. Sci Rep. 2025 Jul 01. 15(1): 20367
    A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model.
    Sulagna Mukherjee, Matthew J Wolan, Mary K Scott, Victoria A Riley, Aidan M Sokolov, David M Feliciano.
      Neural stem cells (NSCs) of the ventricular-subventricular zone (V-SVZ) generate diverse cell types including striatal glia during the neonatal period. NSC progeny uncouple stem cell-related mRNA transcripts from being translated during differentiation. We previously demonstrated that Tsc2 inactivation, which occurs in the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC), prevents this from happening. Loss of Tsc2 causes hyperactivation of the protein kinase mechanistic target of rapamycin complex 1 (mTORC1), altered translation, retention of stemness in striatal glia, and the production of misplaced cytomegalic neurons having hypertrophic dendrite arbors. These phenotypes model characteristics of TSC hamartomas called subependymal giant cell astrocytomas (SEGAs). mTORC1 inhibitors called rapamycin analogs (rapalogs) are currently used to treat TSC and to assess the role of mTORC1 in regulating TSC-related phenotypes. Rapalogs are useful for treating SEGAs. However, they require lifelong application, have untoward side effects, and resistance may occur. They also incompletely inhibit mTORC1 and have limited efficacy. Rapalink-1 is a bitopic inhibitor that links rapamycin to a second-generation mTOR ATP competitive inhibitor, MLN0128. Here we explored the effect of Rapalink-1 on a TSC hamartoma model. The model is created by neonatal electroporation of mice having conditional Tsc2 genes. Prolonged Rapalink-1 treatment could be achieved with 1.5 or 3.0 mg/Kg injected intraperitoneally every five days. Rapalink-1 inhibited the mTORC1 pathway, decreased cell size, reduced neuron dendrite arbors, and reduced hamartoma size. In conclusion, these results demonstrate that cellular phenotypes in a TSC SEGA model are reversed by Rapalink-1 which may be useful to resolve TSC brain hamartomas.
    Keywords:  MTORC1; Neurogenesis; Rapalink-1; SEGA; Subependymal giant cell Astrocytoma; Subependymal nodule; TSC; Tsc2; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1038/s41598-025-08345-z
  2. Am J Physiol Renal Physiol. 2025 Jul 02.
    Kidney organoids demonstrate that PTH1R drives a cystogenic cAMP-pPKA-pCREB axis in developmental Polycystic Kidney Disease.
    Humayra Afrin, Jielu Hao, Usama Qamar, Peter C Harris, Navin Gupta.
      Human pluripotent stem cell-derived kidney organoids have demonstrated utility in modeling kidney development and genetic disease. Autosomal recessive polycystic kidney disease (ARPKD) is an inherited developmental cystic kidney disease of high morbidity and mortality that lacks directed therapy. To overcome the limitations of animal models and stimulate drug discovery, ARPKD organoids have previously been subject to well-described cystogenic mechanisms for use in therapeutic screens. While these studies have validated genotype-phenotype correlations and cystogenic response of ARPKD organoids as similar to existing in vitro models, novel cystogenic mechanisms that expand potential therapeutic targets have yet to be uncovered. Here we use a combination of human induced pluripotent stem cell (iPSC)-derived ARPKD and isogenic wild-type organoids, native kidney and organoid single cell RNA sequencing, decedent human ARPKD tissue, and targeted mechanistic studies to describe PTH1R as a stimulatory G-protein coupled receptor which instigates a cystogenic signaling cascade in developmental cystic kidney disease. Our findings demonstrate the utility of kidney organoids as an in vitro model for pathomechanisms of rare diseases which lack faithful animal models.
    Keywords:  PTH signaling; cystogenesis; kidney organoid; polycystic kidney disease
    DOI:  https://doi.org/10.1152/ajprenal.00056.2025
  3. Sci Rep. 2025 Jul 02. 15(1): 20356
    Transcription factor EB improves hypoxic pulmonary hypertension in fetal rats by suppressing NLRP3 inflammasome activation via induction of mitophagy.
    Chaohong Chen, Zaoye Xie, Dang Ao, Yinhui Chen, Ling Liu, Chengyan Li.
      Persistent pulmonary hypertension of the newborn (PPHN) represents a life-threatening cardiopulmonary condition characterized by hypoxia-driven pulmonary vascular remodeling. While transcription factor EB (TFEB), a master regulator of cellular adaptation to hypoxia, has been implicated in vascular pathologies, its mechanistic role in PPHN remains undefined. This study elucidates the molecular interplay of TFEB in hypoxia-induced PPHN pathogenesis. Fetal rat models of hypoxia-induced PPHN, including untreated hypoxic models and hypoxic models treated with the TFEB inhibitor Eltrombopag (EO), as well as a hypoxia-induced human pulmonary artery endothelial cell (HPAEC) model, were established. Multimodal assessments, including histopathology, qRT-PCR, JC-1 staining, immunofluorescence, flow cytometry, and Western blotting, were employed to evaluate the effects of TFEB on mitophagy and NLRP3 inflammasome. In the hypoxia group, significant thickening of the pulmonary arterioles and right ventricular wall was observed. Immunostaining revealed a significant increase in the relative staining density of TFEB-positive, NLRP3-positive, and LC3-positive cells, alongside elevated expression of mitophagy-proteins and NLRP3 inflammasome-related proteins. TFEB inhibition downregulated the expression of PINK1, TOMM20, COX IV, P62, and LC3II/I ratio, impairing mitophagy, while upregulating eNOS, NLRP3, and GSDMD, thereby enhancing NLRP3 activation and pyroptosis. In the EO group, fetal rats exhibited more pronounced pulmonary arteriole thickening, intensified fluorescence signals for NLRP3, caspase-1, and GSDMD, reduced mitophagy-related protein expression, and further elevated NLRP3 inflammasome-related protein and GSDMD expression. TFEB exerts a protective effect in PPHN by inhibiting NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy, highlighting TFEB's potential as a therapeutic target for hypoxia-induced PPHN.
    Keywords:  Hypoxic pulmonary hypertension; Mitophagy; NLRP3 inflammasome; PINK1/Parkin; Transcription factor EB
    DOI:  https://doi.org/10.1038/s41598-025-07068-5
  4. Am J Case Rep. 2025 Jun 29. 26 e947530
    Differential Diagnosis and a Novel Mutation in Birt-Hogg-Dubé Syndrome: Insights from 2 Cases.
    Lingfang Tu, Yuan Ye, Jianya Zhou, Zhijie Pan.
      BACKGROUND Birt-Hogg-Dube (BHD, OMIM# 135150) syndrome is an inherited autosomal dominant disorder predominantly caused by mutation of FLCN gene, which encodes for folliculin. Although FLCN has been suggested to be involved in the mechanistic target of the rapamycin (mTOR) signaling pathway, the functional role of folliculin is poorly understood. BHD is characterized by skin abnormalities, pulmonary cysts, spontaneous pneumothorax, and kidney neoplasms. BHD can be asymptomatic or occur with symptoms such as cough or shortness of breath, or in extremis after an episode of spontaneous pneumothorax. The purpose of this report is to describe 2 Chinese cases of BHD syndrome, with a literature review of this rare disease. CASE REPORT The patients were 2 Chinese women diagnosed as BHD syndrome, aged 57 and 58 years old. Both patients had a history of pneumothorax, and physical examination revealed skin abnormalities. High-resolution computed tomography (HRCT) demonstrated sparsely-distributed, thin-walled lung cysts. Whole-exome sequencing (WES) analysis identified a mutation in the FLCN gene, confirming the diagnosis of BHD. In addition, a novel pathogenic variant of FLCN mutation in exon 12 (NM_144997.5: c.1341delC, p.Thr448Profs*20) was identified, and this is the first report of an unprecedented FLCN mutation in exon 12. CONCLUSIONS As an autosomal dominant hereditary disease, BHD should be distinguished from emphysema, TSC, LAM, and other diffuse cystic lung diseases for differential diagnosis. When BHD is suspected, identification of pathogenic FLCN germline mutations is essential for a definitive diagnosis.
    DOI:  https://doi.org/10.12659/AJCR.947530
  5. Nat Rev Drug Discov. 2025 Jun 30.
    Targeting the Hippo pathway in cancer.
    Kieran F Harvey, Tracy T Tang.
      The Hippo pathway is a highly conserved signalling network that controls tissue growth and cell fate, responding to physical properties of the tissue microenvironment and cell biological features such as adhesion and polarity. Hippo signalling perturbation is associated with several human diseases, particularly various solid cancers. Hippo pathway-targeted therapies are beginning to emerge for the treatment of cancer, most of which are focused on disrupting the ability of the YAP and TAZ transcription co-activator proteins to promote transcription of genes with their cognate TEAD1-4 DNA binding proteins. Recently, TEAD inhibitors have shown promise in a phase I clinical trial in cancers that are enriched for Hippo pathway mutations, such as mesothelioma. Moreover, Hippo pathway-targeted therapies have great potential to be combined with RAS-MAPK pathway inhibitors, given the close functional relationship that these signalling pathways share in development and disease.
    DOI:  https://doi.org/10.1038/s41573-025-01234-0
  6. Nat Aging. 2025 Jun 30.
    A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
    Tim J Nonninger, Jennifer Mak, Birgit Gerisch, Valentina Ramponi, Kazuto Kawamura, Roberto Ripa, Klara Schilling, Christian Latza, Jonathan Kölschbach, Manuel Serrano, Adam Antebi.
      Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.
    DOI:  https://doi.org/10.1038/s43587-025-00911-4
  7. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
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