bims-raghud 2026-09-20 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–09–20
eight papers selected by
Irene Sambri, TIGEM

Multidimensional Roles of the Transcription Factor EB-Regulated Autophagy-Lysosomal Network in Tumor Drug Resistance.
DFCP1-containing ER microdomains mediate lysosomal membrane repair.
The Crosstalk Between YAP/TAZ and Cancer Metabolism: From Mechanistic Insights to Drug Discovery.
SGLT2 Inhibitors in Cardiovascular-Kidney-Metabolic Syndrome: Drugs Unifying Heart, Kidney, and Metabolism Pharmacotherapy.
Crosstalk Between mTOR and NF-κB Signaling Pathways in Clear Cell Renal Cell Carcinoma.
Kidney fibrosis is mediated by GARP-restricted TGF-β activation in fibroblasts.
Dapagliflozin Prevents Heart Failure With Preserved Ejection Fraction by Inhibiting the Sodium/Hydrogen Exchanger.
Lysosomal signaling pathways influence heart rhythm, and regulate atrial function.

Eur J Pharmacol. 2026 Sep 18. pii: S0014-2999(26)00850-2. [Epub ahead of print] 179368

Multidimensional Roles of the Transcription Factor EB-Regulated Autophagy-Lysosomal Network in Tumor Drug Resistance.

Yue Lu, Yuewen Wang, Daying Sun, Zhangwei Qiao, Zhengchao Wang, Shuliang Song, Junfeng Hou.

  Chemotherapy resistance is a key factor in tumor recurrence and mortality and a barrier to durable therapeutic effectiveness. Besides canonical mechanisms, including target alterations and drug efflux, tumor cells integrate chemotherapy-induced DNA damage, oxidative stress, and metabolic stress into persistent adaptive stress-response programs in which the autophagy-lysosomal pathway (ALP) plays a pivotal role. Transcription factor EB (TFEB), a master transcriptional regulator of the ALP, undergoes stress-responsive nuclear translocation under chemotherapeutic conditions through mechanistic target of rapamycin complex 1 (mTORC1) inhibition, lysosomal Ca2+-calcineurin-mediated dephosphorylation, and related signaling cascades. Nuclear TFEB activates the canonical coordinated lysosomal expression and regulation (CLEAR) network while also engaging broader context-dependent transcriptional programs. Within the autophagy-lysosomal system, CLEAR-dependent regulation promotes autophagosome biogenesis and maturation, autophagosome-lysosome fusion, and lysosomal biogenesis, resulting in enhanced autophagic flux. TFEB-driven enhancement of ALP flux generates multiple adaptive functional outputs, including clearance of damaged cellular substrates, buffering of reactive oxygen species (ROS), recycling of metabolic substrates to meet bioenergetic demands, modulation of cell death thresholds, and reduced effective intracellular drug exposure via lysosomal sequestration, storage, efflux, and intracellular redistribution. This review presents an integrated conceptual platform linking stress-induced TFEB activation, enhanced autophagic flux, downstream functional adaptations, and the emergence of chemotherapeutic resistance. By focusing on the TFEB-ALP axis, this review further identifies a stratified therapeutic intervention model comprising upstream suppression, intermediate pathway blockade, and downstream functional counteraction. These perspectives provide a more systematic and mechanistic understanding for developing precision strategies to overcome chemotherapy resistance by targeting the TFEB-ALP axis.

Keywords:  Drug resistance; autophagic flux; lysosomes; transcription factor EB (TFEB); tumor stress adaptation

DOI:  https://doi.org/10.1016/j.ejphar.2026.179368
Nat Cell Biol. 2026 Sep 15.

DFCP1-containing ER microdomains mediate lysosomal membrane repair.

Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W Schultz, Andreas Brech, James H Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G Gutierrez, Camilla Raiborg, Harald Stenmark.

Lysosomal membrane integrity is essential for preserving cellular homeostasis in response to different stressors. Upon lysosomal membrane permeabilization, cells activate several mechanisms for lysosomal membrane repair, including ESCRT proteins, phosphatidylinositol 4-phosphate (PI4P)-dependent lipid transfer from the endoplasmic reticulum (ER) and conjugation of ATG8 family proteins to single membranes (CASM). The interplay between these pathways and the regulation of the lipid transfer machinery remain incompletely understood. Here we show that phosphatidylinositol 3-phosphate (PI3P)-containing ER domains play a major role in lysosomal membrane repair. PI3P is formed on lysosome-proximal ER domains by the phosphatidylinositol 3-kinase PIK3C3/VPS34 in response to membrane damage, and inhibition or depletion of PIK3C3 inhibits lysosome repair. Mechanistically, the ATPase DFCP1/ZFYVE1 accumulates on lysosome-proximal ER domains by its PI3P binding, triggered by Ca2+ efflux from lysosomes and requiring the ULK1 kinase complex and ER proteins of the VAP family. Downstream of CASM, PI4P, ESCRTs and PI3P, DFCP1 promotes focal accumulation of the lipid channel VPS13C on ER domains proximal to damaged lysosomes to promote their repair. The function and dynamics of DFCP1 depend on its ability to bind and hydrolyse ATP, and absence of DFCP1 compromises cellular resistance to vacuolar damage induced by Listeria monocytogenes. We conclude that DFCP1 mediates concentration of the ER-associated lipid transport machinery at damaged lysosomes to promote their sealing in response to Ca2+ flux and PIK3C3 activation.

DOI: https://doi.org/10.1038/s41556-026-02062-z
Int J Mol Sci. 2026 Aug 23. pii: 7537. [Epub ahead of print]27(17):

The Crosstalk Between YAP/TAZ and Cancer Metabolism: From Mechanistic Insights to Drug Discovery.

Yinhuang Gao, Minghong Chen, Songxia Lin, Min Huang, Jing Jin.

  As the core transcriptional co-activators of the Hippo signaling pathway, YAP and TAZ play essential roles in maintaining tissue homeostasis and in tumorigenesis. Their aberrant activation is frequently observed in human malignancies, and accumulating evidence has identified them as crucial drivers of tumor initiation and progression. YAP/TAZ have been recently recognized as key regulators of cellular metabolic reprogramming, a hallmark of cancer that fuels tumor cell proliferation by rewiring glucose, lipid, amino acid, and nucleotide metabolism. Conversely, the activity of YAP/TAZ is modulated by metabolites such as glucose and lipids, establishing a complex bidirectional regulatory circuit. Therefore, deciphering this intricate crosstalk is of great importance for cancer therapy and drug discovery. In this review, we systematically clarify the interplay between YAP/TAZ and metabolic reprogramming in cancer, delineate the core molecular networks through which YAP/TAZ govern each metabolic pathway, and summarize the current pharmacological inhibitors targeting YAP/TAZ-regulated metabolic networks. Collectively, these findings pave the way for therapeutic approaches targeting YAP/TAZ-driven metabolic vulnerabilities in cancer.

Keywords:  YAP/TAZ; cancer metabolism; metabolic reprogramming; therapeutic target

DOI:  https://doi.org/10.3390/ijms27177537
Am J Cardiovasc Drugs. 2026 Sep 15.

SGLT2 Inhibitors in Cardiovascular-Kidney-Metabolic Syndrome: Drugs Unifying Heart, Kidney, and Metabolism Pharmacotherapy.

Valentina Okhovat, Kamela Lybeshari, Luigi X Cubeddu, Genevieve Hale.

Cardiovascular-kidney-metabolic syndrome describes a complex interplay between cardiovascular disease, chronic kidney disease, and metabolic disorders. Recent randomized controlled trials have demonstrated beneficial effects of SGLT2 inhibitors in patients with this multifaceted condition. This review aims to critically evaluate the available evidence supporting the role of SGLT2 inhibitors in patients with cardiovascular-kidney-metabolic syndrome and familiarize healthcare providers with the evidence surrounding significant renal and cardiac benefits of SGLT2 inhibitors. A comprehensive narrative literature review was conducted using PubMed. Eligible studies included randomized controlled trials, systematic reviews, and meta-analyses published in English between 2018 and 2025, focusing on SGLT2 inhibitors in the context of cardio-renal syndrome and cardio-kidney-metabolic syndrome. Multiple landmark trials have shown that SGLT2 inhibitors significantly reduce the risk of chronic kidney disease progression, MACE, and hospitalization for HF. These benefits were seen in patients both with and without type 2 diabetes. Importantly, SGLT2 inhibitors such as canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin were well tolerated, though caution is advised in volume-depleted patients or those at risk for genitourinary infections. Positive effects, ranging from glycemic control to renoprotective and cardioprotective properties, support SGLT2 inhibitors as first-line therapy in improving clinical outcomes and quality of life in patients affected by this interconnected disease spectrum.

DOI: https://doi.org/10.1007/s40256-026-00829-1
Int J Mol Sci. 2026 Aug 26. pii: 7636. [Epub ahead of print]27(17):

Crosstalk Between mTOR and NF-κB Signaling Pathways in Clear Cell Renal Cell Carcinoma.

Melanie Glueck, Alexandra Lucaciu, Sumedha Inukollu, Rushendhiran Kesavan, Amelie Janssen, Josef Pfeilschifter, Julien Subburayalu, Ramesh K Krishnan, Rajkumar Vutukuri.

  Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation.

Keywords:  NF-κB signaling; cell proliferation; inflammation; mTOR signaling; renal cell carcinoma

DOI:  https://doi.org/10.3390/ijms27177636
JCI Insight. 2026 Sep 17. pii: e203039. [Epub ahead of print]

Kidney fibrosis is mediated by GARP-restricted TGF-β activation in fibroblasts.

Yintong Chen, Weiwei Xu, Jieli Yu, Pei Deng, Nianping Liu, Yinyin Li, Hui Zhou, Hong Zhou, Jianchuan Wang, Bo Zhao, Florian Winau, Fan Fan Hou, Yu Hu.

  TGF-β is a central driver of kidney fibrosis, a common pathological hallmark of chronic kidney disease (CKD). Initiation of TGF-β signaling requires not only its synthesis but also the conversion of latent TGF-β to its bioactive form. However, the mechanisms governing TGF-β activation in the kidney and their contribution to kidney fibrosis remain poorly understood. Glycoprotein A repetitions predominant (GARP) anchors latent TGF-β on the cell surface and facilitates its bioactive release. Here, we show that GARP-mediated TGF-β activation promotes kidney fibrosis. GARP was upregulated in both human and mouse CKD kidneys, predominantly in fibroblasts, and was induced by TNF in an NF-kB-dependent fashion. In multiple mouse models of kidney fibrosis, either global or fibroblast-specific deletion of GARP significantly reduced fibrosis. Mechanistically, GARP enables sustained production of active TGF-β, thereby amplifying fibroblast stimulation. Deletion of GARP in kidney fibroblasts lowered active TGF-β levels and attenuated fibroblast activation, whereas GARP overexpression enhanced TGF-β signaling. Notably, tamoxifen-induced deletion of GARP after fibrosis onset attenuated kidney fibrosis. Together, our findings identify GARP-mediated release of active TGF-β as a critical step in sustaining fibroblast activation during kidney fibrosis and highlight GARP as a promising therapeutic target for CKD.

Keywords:  Fibrosis; Nephrology; Public Health

DOI:  https://doi.org/10.1172/jci.insight.203039
JACC Basic Transl Sci. 2026 Sep 18. pii: S2452-302X(26)00221-4. [Epub ahead of print]11(10): 101698

Dapagliflozin Prevents Heart Failure With Preserved Ejection Fraction by Inhibiting the Sodium/Hydrogen Exchanger.

Man Liu, Hong Liu, Eunji Kim, Gyeoung-Jin Kang, Mitchell C Neumann, Madeline Johnson, Ruthvika Murikinati, Samuel C Dudley.

  Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown protective effects against heart failure with preserved ejection fraction (HFpEF), but SGLT2 is not expressed significantly in the heart. Here, we investigated the mechanism by which the SGLT2 inhibitor dapagliflozin (Dapa) alters HypoMg-associated HFpEF. HypoMg was induced by a low-Mg diet in mice or in a human cardiomyocyte cell line. Three weeks of Dapa treatment prevented HypoMg-induced HFpEF in mice. In RL-14 cardiomyocytes, sodium-hydrogen exchanger 1 (NHE1) overexpression or activation mimicked the cellular effects of HypoMg. Dapa reversed these changes. Dapa prevented cardiac HFpEF by inhibiting cardiomyocyte NHE1 activity and suppressing macrophage activation.

Keywords:  Mg(2+); NHE1; TRPM7; cardiac diastolic dysfunction; inflammation; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.jacbts.2026.101698
Cardiovasc Res. 2026 Sep 19. pii: cvag207. [Epub ahead of print]

Lysosomal signaling pathways influence heart rhythm, and regulate atrial function.

Emily Akerman, Rebecca A Capel, Eva A Rog-Zielinska, Annika Winbo, Daniel Aston, Florian Falter, Razik Bin Abdul Mu-U-Min, Matthew J Read, Samuel J Bose, Pawel Swietach, Jingyu Wang, Alexander D Corbett, Andreas Koschinski, Serena Calamaio, Dario Melgari, Rachele Prevostini, Ilaria Rivolta, Thamali Ayagama, Ifan Jenkin, Jillian N Simon, Funsho E Fakuade, Julius R Pronto, Parveen Sharma, Charlotte Melia, Qianqian Song, Martin J Booth, Frances M Platt, Ming Lei, Svenja Hester, Roman Fischer, Niels Voigt, Ulrich Schotten, Sander Verheule, Aiswarya Dev, Marie Held, Thomas Waring, Antony Galione, Marco Keller, Franz Bracher, Manuela Zaccolo, Derek A Terrar, Rebecca A B Burton.

AIMS: In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca2+) release to augment sarcoplasmic reticulum (SR) Ca2+ sequestration, producing larger Ca2+ transients. However, the role of lysosomal Ca2+ signals in pacemaker activity, a distinct Ca2+-operated function of the sinoatrial node (SAN), or in the atrial myocardium has not been investigated.
METHODS AND RESULTS: Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signaling microdomains between lysosomes and neighboring SR or mitochondria in mouse, and goat tissue. The spatial relationship between lysosomes and other Ca2+-handling organelles are altered in goat atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3'-5'-cyclic adenosine monophosphate (cAMP) in response to lysosomal signaling, adding a novel trigger for cyclic nucleotide signaling.
CONCLUSIONS: Our findings support the hypothesis that lysosomal Ca2+ signaling contributes to regulation of cardiomyocyte cAMP levels and pacemaker activity.

DOI: https://doi.org/10.1093/cvr/cvag207