bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2026–02–08
seven papers selected by
Irene Sambri, TIGEM
  1. Next-generation liquid biopsies: detecting circulating epigenetic changes to identify translocation renal cell carcinoma.
  2. Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.
  3. Targeting mTOR Signaling in Cancer: The Promise of Natural Product-derived Inhibitors.
  4. Redefining SGLT2 inhibitors through cytoprotective mechanisms.
  5. Phosphorylation of Cyclophilin-D is Not Required for Regulation of The Mitochondrial Permeability Transition Pore by GSK3β.
  6. Loss of the translational repressor 4E-BP1 promotes skin carcinogenesis.
  7. Vascularization and maturation of kidney organoids: a comprehensive review of technological trends and challenges.
  1. J Clin Invest. 2026 Feb 02. pii: e201599. [Epub ahead of print]136(3):
    Next-generation liquid biopsies: detecting circulating epigenetic changes to identify translocation renal cell carcinoma.
    Katsuhiro Ito, David A Braun.
      Circulating tumor DNA detection in renal cell carcinoma has long been limited by the disease's low DNA shedding. An aggressive subtype termed translocation renal cell carcinoma (tRCC) is notably more difficult to detect than the common type, clear-cell RCC, in part due to interindividual variability of gene fusions of the transcription factor TFE3, the driving factor in tRCC. In this issue of the JCI, Garinet et al. reported on an epigenomic liquid biopsy approach that identified a TFE3 fusion-associated chromatin signature specific to tRCC. This work demonstrated that fusion-driven epigenomic alterations can be captured noninvasively and used to distinguish tRCC from other renal cancer subtypes. Beyond its diagnostic potential, the approach described by Garinet et al. may enable disease monitoring and subtype classification in other genetically quiet tumors. Epigenomic liquid biopsy is a promising framework to improve diagnostic accuracy and guide personalized management for tRCC.
    DOI:  https://doi.org/10.1172/JCI201599
  2. PLoS One. 2026 ;21(2): e0340957
    Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.
    Katie R Martin, Stephanie L Celano, Jessica D Guillaume, Ryan D Sheldon, Russell G Jones, Jeffrey P MacKeigan.
      Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous, and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we set out to create a quantitative dataset of autophagy across multiple stages in single, living cells, measured under normal growth conditions and during nutrient starvation of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0340957
  3. Anticancer Res. 2026 Feb;46(2): 553-568
    Targeting mTOR Signaling in Cancer: The Promise of Natural Product-derived Inhibitors.
    Pithi Chanvorachote, Chatchai Chaotham, Zin Zin Ei, Preedakorn Chunhacha.
      Recent advances in cancer biology have revolutionized the development of targeted and combination therapies, offering new avenues for improving cancer management. Among the central molecular regulators, the mammalian target of rapamycin (mTOR) plays a pivotal role in orchestrating cell growth, metabolism, and survival. Aberrant activation of mTOR signaling driven by genetic mutations or dysregulation of upstream pathways such as phosphoinositide 3-kinase (PI3K)/AKT has been strongly implicated in cancer progression, metastasis, and therapeutic resistance. Consequently, mTOR has emerged as a promising target for anticancer drug development. Although synthetic mTOR inhibitors, including rapamycin and its analogs (rapalogs), have shown clinical benefits, their limited efficacy and the emergence of resistance have highlighted the need for novel strategies. Natural product-derived mTOR modulators have gained increasing attention due to their multi-targeted mechanisms of action, simultaneously modulating mTOR and its upstream or parallel signaling networks. These compounds exhibit potent anticancer properties, including suppression of tumor growth, induction of apoptosis, and reversal of drug resistance. This review elucidates the biological functions of mTOR in tumorigenesis and delineates its regulatory mechanisms underlying malignant phenotypes. Furthermore, it emphasizes the therapeutic promise of natural products as a rich source of mTOR inhibitors, providing insights for the rational design of innovative cancer therapies and combination regimens.
    Keywords:  Natural product; PI3K/AKT/mTOR signaling pathway; cancer stem cells; epithelial-mesenchymal transition; mTOR inhibitor
    DOI:  https://doi.org/10.21873/anticanres.17969
  4. Eur J Pharmacol. 2026 Feb 04. pii: S0014-2999(26)00129-9. [Epub ahead of print] 178647
    Redefining SGLT2 inhibitors through cytoprotective mechanisms.
    Sanja Stankovic, Zoran Miloradovic, Vladimir Petrovic, Milan Stoiljkovic.
      Sodium-glucose cotransporter-2 (SGLT2) inhibitors have transformed the management of type 2 diabetes by effectively lowering glucose levels through the promotion of glucosuria and natriuresis. Beyond these primary actions, a growing body of experimental and clinical evidence suggests that this drug class exerts a wide range of pleiotropic effects independent of glycemic control. Laboratory studies have shown that SGLT2 inhibitors influence fundamental aspects of cellular metabolism and survival, including the promotion of ketogenesis as an efficient energy source, upregulation of sirtuin 1 that modulates stress resistance and longevity, and attenuation of inflammation and oxidative stress through adenosine monophosphate-activated protein kinase - mechanistic target of rapamycin complex 1 (AMPK - mTORC1) signaling. Collectively, these pathways suggest cytoprotective properties that may underlie the emerging benefits of SGLT2 inhibitors in cardiovascular, renal, and other systemic diseases. This review provides an updated and comprehensive overview of the molecular and cellular mechanisms underlying the extraglycemic actions of SGLT2 inhibitors, links these mechanistic insights to ongoing clinical trials, and underscores their expanding potential for therapeutic repurposing beyond diabetes management.
    Keywords:  SGLT2 inhibitors; cytoprotection; fibrosis; inflammation; ketogenesis; oxidative stress; senescence
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178647
  5. bioRxiv. 2026 Jan 19. pii: 2026.01.15.699680. [Epub ahead of print]
    Phosphorylation of Cyclophilin-D is Not Required for Regulation of The Mitochondrial Permeability Transition Pore by GSK3β.
    Linda Alex, Paula J Klutho, Lihui Song, Manuel Gutiérrez-Aguilar, Christopher P Baines.
      Genetic inhibition of cyclophilin D (CypD) delays the opening of the mitochondrial permeability transition pore (MPTP) and therefore reduces necrotic cell death. Elucidation of factors that impact CypD activity is therefore key to understanding the regulation of MPTP opening. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine kinase that has been shown to modulate MPTP and cell death, potentially through phosphorylation of CypD. Therefore, we hypothesized that the mitochondrial fraction of GSK3β directly phosphorylates CypD and promotes opening of MPTP. Overexpression of full length GSK3β in mouse embryonic fibroblasts sensitized the MPTP and exacerbated oxidative stress-induced necrosis. In contrast, genetic inhibition of GSK3β protected against oxidant-induced cytotoxicity but did not affect the MPTP. Recombinant GSK3β could directly bind to and phosphorylate recombinant CypD. Mass spectrometry revealed several putative GSK3β phosphorylation sites on CypD. However, mutation of these sites did not affect the peptidyl prolyl isomerase activity of CypD and reconstitution of these phosphomutants in CypD-deficient cells increased MPTP sensitivity and oxidative-induced cell death to the same extent as wild-type CypD. Further, targeted overexpression of either wild-type or kinase-inactive GSK3β in the mitochondrial matrix did not impact MPTP or cell death. Moreover, while proteinase-K digestion of cardiac mitochondria showed a significant amount of GSK3β in the mitochondria, it was not localized to the matrix. Finally, overexpression of GSK3β was still able to increase MPTP sensitivity and oxidative stress-induced death in CypD-null cells. Taken together, these data indicate that, while GSK3β can modulate MPTP, this appears to be independent of GSK3β's interaction with, or phosphorylation of CypD.
    DOI:  https://doi.org/10.64898/2026.01.15.699680
  6. Front Pharmacol. 2026 ;17 1742429
    Loss of the translational repressor 4E-BP1 promotes skin carcinogenesis.
    Yibin Zhou, Hanyu Dou, Yifeng Liu, Juan Wang, Xiaolei Ding, Taomin Huang.
       Introduction: Skin squamous cell carcinoma (SCC) arises from dysregulated epidermal homeostasis characterized by aberrant keratinocyte proliferation and pathological angiogenesis. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) functions as a critical suppressor of cap-dependent translation by interacting with eIF4E, thereby constraining protein synthesis and cell growth. However, its role in SCC remains elusive.
    Methods: To address the role of 4E-BP1 function in SCC pathogenesis, we employed a two-stage chemical carcinogenesis model in 4E-BP1-deficient mice.
    Results: 4E-BP1-deficient mice exhibited a significantly increased papilloma burden compared to wild-type controls, accompanied by enhanced keratinocyte proliferation and augmented tumor vascularization. Analysis of human SCC specimens revealed elevated 4E-BP1 phosphorylation together with increased proliferative and angiogenic markers and activation of the mTOR signaling pathway, mirroring molecular features observed in 4E-BP1-deficient tumors.
    Discussion: Collectively, these findings establish 4E-BP1 as a tumor suppressor in skin carcinogenesis that constrains both proliferative and angiogenic processes, underscoring the contribution of dysregulated translation to SCC development.
    Keywords:  4E-BP1; SCC; angiogenesis; mTORC1; proliferation
    DOI:  https://doi.org/10.3389/fphar.2026.1742429
  7. J Artif Organs. 2026 Feb 05. 29(1): 18
    Vascularization and maturation of kidney organoids: a comprehensive review of technological trends and challenges.
    Yusuke Nishimura.
      Chronic kidney disease is a global health issue, and novel therapeutic alternatives to dialysis and kidney transplantation must be developed. Human-induced pluripotent stem cell-derived kidney organoids recapitulate developmental processes and mimic kidney-like structures in vitro and have thus attracted attention for treating chronic kidney disease. However, the limited vascularization and immaturity of human-induced pluripotent stem cell-derived kidney organoids remain major barriers to their clinical application. The latest technological advances and specific challenges in kidney organoid vascularization and maturation were thoroughly examined in this review. Diverse approaches were considered, including coculturing with endothelial cells, in vivo transplantation, applying biomaterials and microfluidic systems, controlling molecular signaling, and metabolic reprogramming. However, issues persist such as low reproducibility, lack of standardization, insufficient functional evaluations, and inadequate safety assessments. Future studies should focus on developing multifactorial and strategies for integrating multiple cell types, establishing maturation assessment criteria, and verifying the long-term functionality and safety of three-dimensional bioprinting technologies. Technologies for the vascularization and maturation of kidney organoids show promise as foundational methods for use innovative regenerative medicine and the development of drug discovery therapies.
    Keywords:  Human induced pluripotent stem cells (hiPSCs); Kidney organoids; Maturation; Regenerative medicine; Vascularization
    DOI:  https://doi.org/10.1007/s10047-026-01545-y
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