bims-raghud 2026-01-04 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–01–04
thirteen papers selected by
Irene Sambri, TIGEM

Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.
TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.
Novel Roles of GDF15 in Alleviating Renal Fibrosis: Promoting Autophagy and Lysosome Biogenesis via Inhibition of the PI3K/Akt/mTOR Pathway.
Current Perspectives on the NF-κB Signaling Axis as a Potential Pharmacological Target in Cardiorenal Syndrome.
Lack of ANKMY2 suppresses kidney cystogenesis in embryonic- and adult-onset polycystic kidney disease.
mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.
Deletion of megalin in kidney tubular epithelium upregulates TGFβ1 signaling, aggravates ischemia/reperfusion kidney injury and accelerates the progression to CKD.
Mitochondrial Permeability Transition Pore: The Cardiovascular Disease's Molecular Achilles Heel.
Reprogramming the Mitochondrion in Atherosclerosis: Targets for Vascular Protection.
Cardiac epigenome in heart development and disease.
Organoid-based drug screening identifies homoharringtonine as a therapeutic agent for anaplastic thyroid cancer via TFEB-mediated lysosomal dysfunction.
GATOR1 complex controls cisplatin sensitivity.
A novel mechanism of lysosome-dependent microautophagy of er exit sites.

iScience. 2025 Dec 19. 28(12): 114204

Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.

Jong Shin, Khaled Tighanimine, Yann Cormerais, Dean M Rosenthal, Pratima Niroula, Samuel C Lapp, Krystle C Kalafut, Madi Y Cisse, Sandra Schrötter, Brendan D Manning.

  The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a sensor of growth signals that control cell growth, has been studied mainly in proliferating cells. Primary cilia are sensory organelles present on most quiescent cells and are essential for receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences primary cilia growth. Here, we show that mTORC1 promotes cilia elongation without affecting ciliogenesis by suppressing autophagy. Inhibiting mTORC1 through pharmacological, nutritional, or genetic interventions shortened primary cilia, whereas activation of the pathway elongated them. Furthermore, pharmacological or genetic inhibition of autophagy-a key downstream process blocked by mTORC1-elongated primary cilia and rendered them resistant to mTORC1 inhibition. These mTORC1-mediated effects extend to mouse neurons ex vivo and in vivo. Thus, the mTORC1-mediated regulation of autophagy controls primary cilia length and may contribute to diseases in which ciliary function is altered, referred to as ciliopathies.

Keywords:  Cell biology; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2025.114204
Sci Adv. 2026 Jan 02. 12(1): eaea9302

TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.

Maria Iavazzo, Laura Cinque, Sophie Levantovsky, Castrese Morrone, Jlenia Monfregola, Andrea Raimondi, Elena Polishchuk, Rossella De Cegli, Diego Carrella, Edoardo Nusco, Luigi Ferrante, Francesca Sacco, Lisa B Frankel, Christian Behrends, Carmine Settembre.

(Macro)autophagy is a conserved cellular degradation pathway that delivers substrates to lysosomes via autophagosomes. Among various physiological stimuli, nutrient starvation is the most potent inducer of autophagy. In response to starvation, transcription factor EB (TFEB) is activated and up-regulates a broad set of autophagy-related genes. However, the mechanisms by which TFEB promotes autophagosome biogenesis remain incompletely understood. Here, we demonstrate that TFEB-mediated transcriptional induction of sequestosome 1 (SQSTM1; p62) triggers the formation of SQSTM1-positive bodies that recruit essential autophagy factors, thereby initiating autophagosome biogenesis. Genetic disruption of TFEB-dependent SQSTM1 regulation markedly impairs starvation-induced autophagy, underscoring the critical role of the TFEB-SQSTM1 axis in the autophagic response to nutrient stress. Furthermore, we show that these SQSTM1 bodies contain ubiquitinated ribosomal proteins and that TFEB promotes ribosomal protein ubiquitination by inducing the E3 ubiquitin ligase ZNF598. Collectively, our findings uncover a transcriptionally coordinated mechanism that regulates both autophagosome biogenesis and substrate ubiquitination, facilitating efficient cargo clearance during starvation-induced autophagy.

DOI: https://doi.org/10.1126/sciadv.aea9302
J Cell Mol Med. 2026 Jan;30(1): e70951

Novel Roles of GDF15 in Alleviating Renal Fibrosis: Promoting Autophagy and Lysosome Biogenesis via Inhibition of the PI3K/Akt/mTOR Pathway.

Youqi Li, Jinge Gu, Danping Tao, Haoyang Wu, Chen Yang, Yongjun Shi, Chengwen Huang, Boxun Luo, Jun Zhang.

  Tubulointerstitial fibrosis (TIF) significantly contributes to the development of end-stage renal disease (ESRD) in chronic kidney disease (CKD). However, the underlying mechanisms driving its development remain poorly understood, thereby impeding the development of effective prevention and treatment strategies. Although growth differentiation factor 15 (GDF15) has been implicated in kidney diseases, its specific relationship and mechanisms in the context of renal TIF remain unclear. In this study, we investigated the role and mechanisms of GDF15 in TIF using a mouse model of unilateral ureteral obstruction (UUO) and human tubular epithelial cells (HK2) stimulated by transforming growth factor-β1 (TGF-β1). Our findings demonstrated a downregulation of GDF15 expression in TIF. The upregulation of GDF15 mitigates renal TIF and reduces macrophage infiltration, whereas its downregulation exacerbates these conditions. Further analysis revealed that GDF15 promotes autophagy and lysosome biogenesis via the PI3K/Akt/mTOR signalling pathway, conferring a protective effect against TIF. In summary, our study demonstrated a negative correlation between GDF15 expression and renal TIF, highlighting its protective role in TIF. Moreover, GDF15 was found to promote autophagy and resolution of TIF through the PI3K/Akt/mTOR signalling pathway.

Keywords:  GDF15; PI3K/Akt/mTOR pathway; autophagy; macrophage infiltration; tubulointerstitial fibrosis

DOI:  https://doi.org/10.1111/jcmm.70951
Drug Des Devel Ther. 2025 ;19 11557-11583

Current Perspectives on the NF-κB Signaling Axis as a Potential Pharmacological Target in Cardiorenal Syndrome.

Qian Liu, Xinting Wang, Peipei Cheng, Tianshu Yang, Chen Wang, Hua Zhou.

  Cardiorenal syndrome (CRS) is a disease involving two vital organs, the heart and the kidney, which has been increasingly recognized in recent years. The treatment of CRS is highly challenging due to its complex nature, rapid progression, poor prognosis, and high mortality rate. As a protein complex, nuclear factor kappa-B (NF-κB) regulates the transcription of target genes by entering the nucleus and affects cardiac and renal functions through its involvement in inflammatory reactions and oxidative stress. By evaluating established preclinical and clinical research on CRS to date, we explored the potential of NF-κB inhibition to exert unique cardiorenal protective effects as a novel treatment for CRS. In this review, we have synthesized recent advances in the structure and function of NF-κB within the cardiovascular and renal systems, and explored the mechanistic involvement of NF-κB in CRS. Innovatively, we have identified natural compounds that dually inhibit NF-κB activity in both cardiac and renal tissues, thereby conferring concurrent protection to both organs. Furthermore, we discuss the translational potential and clinical applicability of NF-κB-targeted pharmacology, which may provide critical insights for developing novel therapeutics against CRS.

Keywords:  NF-κB; cardiorenal syndrome; inflammation; natural compounds; oxidative stress

DOI:  https://doi.org/10.2147/DDDT.S559816
PLoS Genet. 2025 Dec 31. 21(12): e1012008

Lack of ANKMY2 suppresses kidney cystogenesis in embryonic- and adult-onset polycystic kidney disease.

Sun-Hee Hwang, Kyungsuk Choi, Hemant Badgandi, Kevin A White, Yu Xun, Owen M Woodward, Feng Qian, Saikat Mukhopadhyay.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive bilateral cyst formation. Multiple cellular pathways including second messenger cAMP signaling are dysregulated in ADPKD, but mechanisms initiating cysts are unknown. ADPKD is caused by mutations in PKD1/PKD2 genes encoding for polycystins that localize to primary cilia-nonmotile, microtubule-based dynamic compartments sensing extracellular chemical/mechanical signals. The compact cylindrical structure of cilia enables tunable signaling amplification regulatable by ciliary length. Severe cystogenesis from polycystin loss is cilia dependent and ciliary elongation is common in cystic epithelia. However, uncoupling the cilium-specific signals repressed by polycystins from downstream cystogenic pathways has proven challenging. Here we aim to understand roles of compartmentalized cAMP signaling in cystogenesis and ciliary length control. We investigated ANKMY2, an Ankyrin repeat MYND domain protein involved in maturation and ciliary localization of membrane adenylyl cyclases-enzymes generating cAMP. In kidney-specific Ankmy2/Pkd1 knockout mice, loss of ANKMY2 suppressed early postnatal cystogenesis and significantly extended survival in an embryonic-onset Pkd1 deletion model. Similarly, in an adult inducible Pkd1 knockout model, ANKMY2 deficiency reduced cyst burden. Mechanistically, ANKMY2 controlled the ciliary trafficking of multiple adenylyl cyclases in mouse and human kidney epithelial cells without disrupting cilia while retaining cellular pools. Ciliary elongation began in dilatated tubules of adult onset ADPKD mice and further increased in cystic kidneys. Both initial and progressive phases of cilia lengthening were ANKMY2-dependent. Our findings indicate that ciliary adenylyl cyclase signaling likely promotes cilia-dependent cyst initiation distinct from cyst progression involving cellular cAMP. Importantly, kidneys lacking ANKMY2 did not show ciliary elongation despite elevated cAMP, suggesting that cilia lengthening during cyst progression could be contingent upon pre-cystic ciliary regulation. These results suggest a critical role for compartmentalized adenylyl cyclase signaling in ADPKD pathogenesis and a framework for identifying ciliary effectors and early subcellular events in cystogenesis.

DOI: https://doi.org/10.1371/journal.pgen.1012008
Signal Transduct Target Ther. 2025 Dec 30. 10(1): 428

mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.

Hanxiao Zhang, Xia Xiao, Zhenrui Pan, Svetlana Dokudovskaya.

The mammalian target of rapamycin (mTOR) pathway is a central regulator of cellular growth, metabolism, and homeostasis, integrating a wide array of intracellular and extracellular cues, including nutrient availability, growth factors, and cellular stress, to coordinate anabolic and catabolic processes such as protein, lipid, and nucleotide synthesis; autophagy; and proteasomal degradation. The dysregulation of this signaling hub has broad implications for health and disease. To commemorate the 50th anniversary of the discovery of rapamycin, we provide a comprehensive synthesis of five decades of mTOR research. This review traces the historical trajectory from the early characterization of the biological effects of rapamycin to the elucidation of its molecular target and downstream pathways. We integrate fundamental and emerging insights into the roles of mTOR across nearly all domains of cell biology and development, with a particular focus on the expanding landscape of therapeutic interventions targeting this pathway. Special emphasis is placed on the crosstalk between mTOR signaling and mitochondrial regulation, highlighting the mechanisms by which these two metabolic hubs co-regulate cellular adaptation, survival, and disease progression. The dynamic interplay between mTOR and mitochondrial networks governs key aspects of bioenergetics, redox balance, and cell fate decisions and is increasingly implicated in pathophysiological contexts ranging from cancer and aging to neurodegenerative and immune disorders.

DOI: https://doi.org/10.1038/s41392-025-02493-4
Am J Pathol. 2025 Dec 30. pii: S0002-9440(25)00461-4. [Epub ahead of print]

Deletion of megalin in kidney tubular epithelium upregulates TGFβ1 signaling, aggravates ischemia/reperfusion kidney injury and accelerates the progression to CKD.

Qingtian Li, Jeffery Li, Li Tan, Michael Holliday, Emily Ji, Sandhya Thomas, Jizhong Cheng, M N V Ravi Kumar, David Sheikh-Hamad.

  Ischemic acute kidney injury (AKI) may accelerate the progression to end-stage kidney disease (ESKD). We have shown megalin shuttles stanniocalcin-1 (promotes mitochondrial anti-oxidant defenses) to the mitochondria through retrograde-early endosomes-to-Golgi pathway, and knockout of megalin in cultured cells impairs glycolysis and mitochondrial respiration. We sought to determine kidney phenotype after I/R kidney injury in mice with tubular epithelium-specific deletion of megalin. Mice (on C57B/6 background) with conditional tubular epithelium-specific knock-out (KO) of megalin (tLrp2KO) and mice with combined conditional tubular epithelium-specific KO of megalin and overexpression of STC1 (tLrp2KO;tSTC1O) were subjected to 30 minutes ischemia (clamping of renal pedicles) followed by reperfusion for 1, 3,10, 45 and 90 days. Serum creatinine was measured and kidneys were harvested for analysis. After ischemia/reperfusion (I/R) and compared with control mice, tLrp2KO mice displayed worse AKI, severe and persistent inflammation, diminished tubular epithelial cell proliferation, upregulation of TGFβ1 signaling, fibrosis and accelerated progression to chronic kidney disease (CKD). Kidney injury was not rescued in tLrp2KO;tSTC1O mice, consistent with megalin-dependent renal protection by STC1. Freshly isolated proximal tubule fragments from tLrp2KO mice or cultured proximal tubule epithelial cells (BUMPT) with megalin KO displayed activation of TGFβ1 signaling, consistent with modulation of TGFβ1 signaling by megalin. In conclusion, tubular epithelium-specific deletion of megalin aggravates I/R kidney injury, upregulates TGFβ1 signaling and accelerates CKD progression.

Keywords:  Acute kidney injury; Megalin; inflammation; mitochondria; stanniocalcin-1

DOI:  https://doi.org/10.1016/j.ajpath.2025.11.011
Biomedicines. 2025 Dec 09. pii: 3014. [Epub ahead of print]13(12):

Mitochondrial Permeability Transition Pore: The Cardiovascular Disease's Molecular Achilles Heel.

Salvatore Nesci, Speranza Rubattu.

  The mitochondrial permeability transition pore (mPTP) plays a central role in myocardial injury. Upon reperfusion after myocardial infarction, oxidative stress, calcium overload, and ATP depletion promote mPTP opening, leading to mitochondrial dysfunction, cell death, and infarct expansion. This process affects various cardiac cell types differently, contributing to complex pathological remodelling. Key mitochondrial events, such as disruption of bioenergetics parameters, impaired mitophagy, and oxidative stress, drive regulated cell death. Emerging therapies targeting mitochondrial biology, dynamics, and transplantation offer promising strategies to mitigate damage and improve cardiac outcomes. Considering the potential to improve cardiac outcomes and redefine therapeutic approaches in the management of cardiovascular disease, mPTP modulation represents a compelling therapeutic target in myocardial infarction and ischemia-reperfusion injury management.

Keywords:  cardiovascular diseases; cell death; mitochondria; mitochondrial permeability transition pore; myocardial infarction

DOI:  https://doi.org/10.3390/biomedicines13123014
Antioxidants (Basel). 2025 Dec 05. pii: 1462. [Epub ahead of print]14(12):

Reprogramming the Mitochondrion in Atherosclerosis: Targets for Vascular Protection.

Patrycja Anna Glogowski, Federica Fogacci, Cristina Algieri, Antonia Cugliari, Fabiana Trombetti, Salvatore Nesci, Arrigo Francesco Giuseppe Cicero.

  Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, with a substantial proportion of events occurring prematurely. Atherosclerosis (AS), the central driver of cardiovascular pathology, results from the convergence of metabolic disturbances, vascular inflammation, and organelle dysfunction. Among intracellular organelles, mitochondria have emerged as critical regulators of vascular homeostasis. Beyond their canonical role in adenosine triphosphate (ATP) production, mitochondrial dysfunction-including impaired mitochondrial oxidative phosphorylation (OXPHOS), excessive generation of reactive oxygen species (ROS), accumulation of mitochondrial DNA (mtDNA) damage, dysregulated dynamics, and defective mitophagy-contributes to endothelial dysfunction, vascular smooth muscle cell (VSMC) phenotypic switching, macrophage polarization, and ultimately plaque initiation and destabilization. These insights have established the rationale for mitochondrial "reprogramming"-that is, the restoration of mitochondrial homeostasis through interventions enhancing biogenesis, dynamics, and quality control-as a novel therapeutic paradigm. Interventions that enhance mitochondrial biogenesis, restore mitophagy, and rebalance fission-fusion dynamics are showing promise in preclinical models of vascular injury. A growing array of translational strategies-including small-molecule activators such as resveratrol and Mitoquinone (MitoQ), gene-based therapies, and nanoparticle-mediated drug delivery systems-are under active investigation. This review synthesizes current mechanistic knowledge on mitochondrial dysfunction in ASand critically appraises therapeutic approaches aimed at vascular protection through mitochondrial reprogramming.

Keywords:  atherosclerosis (AS); endothelial dysfunction; mitochondrial reprogramming; mitophagy; nanoparticle-based therapies; vascular protection; vascular smooth muscle cells (VSMC)

DOI:  https://doi.org/10.3390/antiox14121462
Nat Rev Cardiol. 2026 Jan 02.

Cardiac epigenome in heart development and disease.

Patrick Laurette, Ralf Gilsbach.

Genetic and acquired forms of heart disease are leading causes of death worldwide. The epigenome, which governs cellular identity by modulating the accessibility of genetic regulatory elements, is established during development by transcription factors and has a pivotal role in the execution of cellular programmes. The epigenetic layers include DNA methylation, histone modifications and chromatin accessibility, which are dynamically regulated during development and in response to stress. Advances in single-cell and cell type-resolved epigenome analyses have provided unprecedented insights into the heterocellular nature of organs such as the heart, via the identification of epigenetic mechanisms and disease-associated epigenetic alterations in cardiomyocytes and other cardiac cell types. Chromatin remodelling, driven by specific modifiers, transcription factors and chaperones, orchestrates cardiac gene expression and contributes to disease manifestation and progression. Understanding how to modulate these epigenetic pathways in a cell type-specific manner offers promising avenues for therapeutic intervention, including epigenome editing for targeted modulation of regulatory elements. In this Review, we highlight studies decoding the various layers of the cardiac epigenome, emphasizing the interplay between cell type-specific mechanisms, describe emerging methods to study the cardiac epigenome, and discuss the translational potential of targeting epigenetic mechanisms for the prevention and treatment of cardiac diseases.

DOI: https://doi.org/10.1038/s41569-025-01223-1
Cell Oncol (Dordr). 2025 Dec 29. 49(1): 5

Organoid-based drug screening identifies homoharringtonine as a therapeutic agent for anaplastic thyroid cancer via TFEB-mediated lysosomal dysfunction.

Xinyue Zhang, Zhihui Li, Jiaye Liu, Rui Huang.

   PURPOSE: Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy with unmet clinical needs for novel therapeutic agents. Most prior studies have relied on limited ATC cell lines, which fail to recapitulate tumor heterogeneity. This study aimed to discover novel agent for ATC via patient-derived organoid (PDO)-based drug screening and investigate the underlying therapeutic mechanism.
METHODS: Drug screening was performed on ATC organoids using a drug library of stem cell differentiation compounds. RNA-sequencing identified pathway-level mechanisms, while structure-based molecular docking prioritized target proteins.
RESULTS: Using a library of stem cell differentiation compounds, we identified homoharringtonine (HHT) as a potent inhibitor for ATC growth in vitro and in vivo. Mechanistically, this effect was mediated by lysosomal dysfunction, which blocked autophagosome-lysosome fusion and triggered cytotoxicity. Furthermore, HHT exhibited high affinity for the PI3K p110 subunit, activating the PI3K-AKT-mTOR pathway to phosphorylate transcription factor EB, retaining it in the cytoplasm and thereby inhibiting lysosomal biogenesis.
CONCLUSION: Our study demonstrates the utility of cancer organoids in drug discovery and identifies HHT as a promising therapeuticagent for ATC.

Keywords:  Anaplastic thyroid cancer; Drug repurposing; Drug screening; Lysosomal autophagy; Patient-derived organoid

DOI:  https://doi.org/10.1007/s13402-025-01132-y
Cell Death Dis. 2025 Dec 30.

GATOR1 complex controls cisplatin sensitivity.

Zhenrui Pan, Hanxiao Zhang, Xia Xiao, Catherine Brenner, Svetlana Dokudovskaya.

Cisplatin administration is the primary chemotherapy approach for many epithelial cancers. However, resistance to this drug poses a significant challenge to effective treatment. Despite the identification of numerous factors associated with resistance, reliable biomarkers predicting drug response remain elusive. Previously, low expression of the NPRL2 tumor suppressor was linked to cisplatin resistance. NPRL2, along with NPRL3 and DEPDC5, forms the GATOR1 complex, an upstream regulator of the mTORС1, the function of which is perturbed in many cancers, particularly those resistant to cisplatin. Here, we compare non-cancerous bronchial epithelium BEAS-2B cells with GATOR1 deletions, serving as a model of intrinsic cisplatin resistance, with non-small cell lung cancer lines A549, H460, and H1975 with acquired resistance to the drug. We found that deletion of any GATOR1 member, not solely NPRL2, promotes cisplatin resistance, whereas their overexpression renders cells sensitive to the drug. In cells with GATOR1 deletions, expression of the ATP7A transporter required for cisplatin efflux is increased, while expression of cisplatin influx transporters CTR2 and LRRC8A is downregulated, especially after treatment with the drug. This hinders drug accumulation in cells, resulting in the formation of fewer cisplatin-DNA adducts. Simultaneously, these cells exhibit enhanced DNA damage response and mTORC1 activity. Overexpression of GATOR1 components and/or concomitant treatment with an mTORC1 inhibitor restores sensitivity to cisplatin. Transcriptomic analysis of GATOR1-deleted BEAS-2B cells, treated or not with the drug, identifies new signatures important for understanding GATOR1 function and its role in cisplatin resistance. Thus, GATOR1 not only participates in the cellular response to amino acid availability but also plays a role in resistance to DNA-damaging anticancer drugs. This novel function of GATOR1 should be taken into account when developing new strategies to combat chemoresistance.

DOI: https://doi.org/10.1038/s41419-025-08392-4
Autophagy. 2025 Dec 31.

A novel mechanism of lysosome-dependent microautophagy of er exit sites.

Dibyendu Bhattacharyya, Daniel J Klionsky.

  Endoplasmic reticulum (ER) exit sites (ERES) serve as essential hubs for the packaging and export of secretory proteins into the COPII vesicular pathway. Previous studies have shown that ERES are dynamic and capable of adapting to stress, but the molecular details controlling their degradation under nutrient stress conditions were largely unknown. The study by Liao et al. (2024) introduces a new mechanism in which ERES are degraded through lysosome-dependent microautophagy in response to nutrient stress. This process is uniquely facilitated by COPII components, the calcium-binding adaptor ALG2, and the ESCRT machinery. The authors demonstrate that inhibiting MTOR triggers calcium release from lysosomes, which then recruits ALG2, leading to SEC31 ubiquitination and subsequently promoting PDCD6IP/ALIX-ESCRT-dependent lysosomal engulfment of ERES. This research reveals an unexplored pathway for the quality control and recycling of secretory machinery, thereby improving our understanding of ER turnover and establishing a mechanistic link between nutrient sensing, autophagy, and remodeling of the secretory pathway.

Keywords:  Autophagy; COPII; ESCRT; er exit sites; microautophagy

DOI:  https://doi.org/10.1080/15548627.2025.2608387