bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2026–10–04
fifteen papers selected by
Irene Sambri, TIGEM
  1. Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.
  2. A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
  3. Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
  4. Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.
  5. Birt-Hogg-Dubé syndrome: From molecular mechanisms to emerging systemic therapeutic strategies.
  6. The Activation of the Transcription Factor NRF2 in Epithelial Cells Lining the Kidney Cysts in Tuberous Sclerosis Complex (TSC): The Interplay of Fumarate Hydratase 1, KEAP1, and NRF2 in Kidney Cystogenesis.
  7. Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes.
  8. Establishment of an Animal Model of Type 2 Cardiorenal Syndrome.
  9. Polymeric alpha-1 antitrypsin perturbs Paneth cell proteostasis and exacerbates intestinal inflammation.
  10. deptor disruption induces axonal and behavioral abnormalities through altered cholesterol metabolism in zebrafish.
  11. S-Nitrosylation of glycogen phosphorylase regulates nuclear glycogenolysis and is impaired in metabolic liver disorders.
  12. The Polycystic Kidney Disease Cyst Transcriptome Defined by Integrating Spatial, Single Nuclear, and Bulk Transcriptomics.
  13. Tonicity drives collecting duct maturation in the mammalian kidney.
  14. Lysosomal multi-omics reveals altered sphingolipid catabolism associated with lysosomal dysfunction in the aging brain.
  15. SGLT2 inhibitors: mechanisms, physiology and pharmacology, and clinical applications.
  1. Cell Death Differ. 2026 Sep 30.
    Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.
    Marco Ferniani, Irene Sambri, Tuong Huynh, Rossella Pennella, Gennaro Tufano, Niculin J Herz, Barbara Rossi, Antonella Iannaccone, Francesco Trepiccione, Alessia Calcagnì, Andrea Ballabio.
      Birt-Hogg-Dubé (BHD) and Tuberous Sclerosis (TSC) are inherited cancer syndromes associated with kidney cystogenesis and tumorigenesis and caused by mutations of the folliculin (FLCN) and TSC1/2 genes, respectively. We and others previously showed that Transcription Factors EB (TFEB) and E3 (TFE3) are the main drivers of the kidney phenotypes observed in mouse models of these conditions. These transcription factors are also responsible for the feedback hyperactivation of the mechanistic Target of Rapamycin Complex 1 (mTORC1), a known tumorigenic factor. This raises the question of whether TFEB/TFE3 exert their oncogenic activity by inducing mTORC1 or by mTORC1-independent pathways. To address this question, we generated kidney-specific mouse models in which we knocked out factors that differentially control mTORC1 and TFEB/TFE3, thus uncoupling their activities. Specifically, we generated three kidney-specific conditional knockout lines: (1) Depdc5-KO mice in which loss of GATOR1 activity leads to mTORC1 hyperactivation and TFEB/TFE3 inhibition, (2) RagC-KO mice in which TFEB/TFE3 are constitutively active and mTORC1 activity is partially inhibited due to impaired Rag heterodimer formation, and (3) Flcn/RagC double KO mice to test whether mTORC1 inhibition induced by RagC loss ameliorates the aggressive kidney phenotype of FLCN KO mice. Comparison between these models revealed that mTORC1 hyperactivation is a key driver of cystogenesis and tumorigenesis, while TFEB/TFE3 constitutive activation further enhances and accelerates pathology by establishing a transcriptional program that integrates metabolic and stress-response pathways. Together, our findings define an oncogenic mechanism by which both mTORC1 and TFEB/TFE3 hyperactivation cooperate in kidney tumorigenesis.
    DOI:  https://doi.org/10.1038/s41418-026-01881-9
  2. Nature. 2026 Sep 30.
    A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
    Alessandra Esposito, Ibrahim Bayramoglu, Chiara Varriale, Maria Pia Cavaliere, Maria Elsa Brunetti, Rossella Agostinis, Rachel M Jansen, Dan A Tudorica, Yongjia Duan, Martina Spacci, Alessia Calcagnì, Carolin D Strobl, Verena Passerini, Fabrizio Andreone, Jlenia Monfregola, Julia Richter, Francesca Sacco, Wolfram Klapper, Oliver Weigert, Andrea Ballabio, Roberto Zoncu, James H Hurley, Joern Dengjel, Gennaro Napolitano.
      Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-026-11093-3
  3. Nat Commun. 2026 08 31. pii: 10359. [Epub ahead of print]17(1):
    Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
    Krystle C Kalafut, Yann Cormerais, Madi Y Cissé, Samuel C Lapp, Karen E Inouye, Gökhan S Hotamışlıgil, Brendan D Manning.
      The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, and aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well-defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, studies employing a liver-specific genetic mouse model demonstrate that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, postprandial activation of hepatic mTORC1 requires dietary protein, which dictates the insulin-responsiveness of the pathway. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity, despite overt impairments in insulin and glucose homeostasis, and blocking hepatic AKT-TSC-mTORC1 signaling did not affect these metabolic phenotypes. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.
    DOI:  https://doi.org/10.1038/s41467-026-77216-6
  4. bioRxiv. 2026 Sep 25. pii: 2026.09.23.753918. [Epub ahead of print]
    Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.
    Mathew B McDougal, Abigail Sandoval, Mike Kinter, Antrix Jain, Sukyeong Lee, Sung Yun Jung, Wan Hee Yoon.
      We previously discovered that a de novo variant p.R528W in ATAD3A , encoding a mitochondrial membrane-anchored protein, causes a human neurological syndrome. While ATAD3A mutations induce aberrant lysosomal expansion accompanied by undigested material in the lysosomes, how mutant ATAD3A disrupts lysosomal homeostasis and whether this contributes to neurodevelopmental defects remain unknown. Here we show that pathogenic ATAD3A p.R528W expression disrupts the mTORC1-TFEB axis as revealed by dysregulation of mTORC1 substrate phosphorylation, TFEB nuclear localization, and CLEAR gene activation associated with lysosomal biogenesis. ATAD3A binds to lysosome-localized Rag C/D GTPases, which constitute a platform for TFEB recruitment, with pathogenic variants increasing this association and thereby decreasing lysosomal localization of Rag GTPases. Importantly, overexpression of RagC or RagD restores TFEB phosphorylation in human cells expressing p.R528W, and RagC- D overexpression or TFEB/Mitf knockdown rescues lysosomal expansion and neurodevelopmental defects in Drosophila . These data indicate that disrupted Rag GTPase recruitment to lysosomes and subsequent aberrant TFEB/Mitf activation contribute to neurodevelopmental and lysosomal phenotypes caused by pathogenic mutations in ATAD3A . Our work reveals a novel role for the mitochondrial resident protein ATAD3A in modulating lysosomal homeostasis through regulation of the mTORC1-TFEB axis, providing a mechanistic link between impaired mitochondrial and lysosomal homeostasis in a neurodevelopmental disorder.
    DOI:  https://doi.org/10.64898/2026.09.23.753918
  5. Med Clin (Barc). 2026 Sep 29. pii: S0025-7753(26)00278-2. [Epub ahead of print]166(11): 107627
    Birt-Hogg-Dubé syndrome: From molecular mechanisms to emerging systemic therapeutic strategies.
    Sabela Castañeda Pérez, Ana Fernández Argüeso, Adriano Quiroga Castiñeira, Eide Diana Alves Pereira.
      Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline mutations in the FLCN gene. It is characterized by pulmonary cysts with recurrent pneumothorax, renal tumors, and cutaneous lesions, with marked phenotypic variability. This review summarizes current evidence on the molecular basis and clinical manifestations of BHD, highlighting the role of folliculin in cellular metabolism through the AMPK-mTOR signaling pathway and related mechanisms involved in tumorigenesis. From a clinical perspective, diagnosis is often challenging and relies on combined genetic and phenotypic criteria. Management is currently based on surveillance strategies, particularly for early detection of renal cancer. Emerging therapeutic approaches targeting mTOR signaling, metabolic pathways, and transcriptional regulators show promising results in preclinical models, although their clinical impact remains to be established.
    Keywords:  AMPK; Birt–Hogg–Dubé síndrome; FLCN; Metabolic regulation; Regulación metabólica; Síndrome de Birt-Hogg-Dubé; Targeted therapies; Terapias dirigidas; Vía mTOR; mTOR pathway
    DOI:  https://doi.org/10.1016/j.medcli.2026.107627
  6. bioRxiv. 2026 Sep 23. pii: 2026.09.22.753536. [Epub ahead of print]
    The Activation of the Transcription Factor NRF2 in Epithelial Cells Lining the Kidney Cysts in Tuberous Sclerosis Complex (TSC): The Interplay of Fumarate Hydratase 1, KEAP1, and NRF2 in Kidney Cystogenesis.
    Sharon Barone, Kamyar Zahedi, Manoocher Soleimani.
       Background: Tuberous Sclerosis Complex (TSC) is caused by inactivating mutations in either the TSC1 or TSC2 genes, leading to activation of the mammalian target of rapamycin complex 1 (mTORC1) and unhindered cell growth and proliferation. The epithelium of TSC renal cysts in both mice and humans is composed of proliferating A-intercalated (A-IC) cells. The exact molecular mechanism of kidney cystogenesis in TSC remains speculative.
    Hypothesis: Superfluous cell proliferation driven by mTORC1 activation increases metabolic demand, causing oxidative stress and excess reactive oxygen species. If unchecked, this overwhelms antioxidant defenses and causes cell death. In TSC kidney cystogenesis, Nuclear Factor Erythroid 2-Related Factor 2 (NFE2L2), also known as NRF2, serves as the "master regulator" of antioxidant and anti-inflammatory responses, enabling cells to survive and proliferate by clearing the toxic environment and supplying nutrients and fuel.
    Results: RNA-seq and proteomics, along with western blot analysis, showed robust downregulation of Fumarate Hydrase 1 (FH1) and upregulation of NRF2, STAT3, and HIF1α in kidneys from TSC mice with moderate or heavy cyst burden. Confocal microscopy and immunohistochemical staining on kidney sections, and/or western blot studies on nuclear and cytoplasmic fractions, showed nuclear localization of NRF2, STAT3, and HIF1α. In cyst-lining cells in TSC mouse models, FH1 downregulation was associated with inactivating succination of KEAP1 in immunoprecipitation experiments, promoting NRF2 nuclear localization in A-IC cells lining the cysts. NRF2 nuclear localization was associated with ectopic induction of the glutamine transporter SLC38A3 (SNAT3) on the basolateral membrane and activation of the NH 3 /NH 4 + transporters RHCG and RHBG in A-IC cells lining the cysts. Twenty-four h urine NH 3 /NH 4 + excretion rates increased significantly in Tsc1 KO vs. WT mice. The activation of NRF2, STAT3, and HIF1α can drive metabolic reprogramming and activate survival genes in proliferating cells. Together with SLC38A3 induction and upregulation of other glutamine and NH 3 /NH + transporters, these factors activate glutaminolysis and aerobic glycolysis, supplying nutrients to proliferating cystic epithelial cells and supporting cyst expansion in TSC. Consistent with this central role for glutaminolysis in kidney cystic epithelium and TSC cystogenesis, we find a significant reduction in kidney cyst burden in Tsc1 KO mice on a glutamine-free diet.
    Conclusions: NRF2 plays a critical role in antioxidant defense. Along with STAT3 and HIF1α, NRF2 is a key player in metabolic reprogramming through glutaminolysis, which supplies nutrients to proliferating cystic epithelial cells and supports cyst expansion in TSC. These findings suggest that inhibiting or inactivating NRF2, alone or in combination with HIF1α or STAT3, may represent a potential treatment strategy for kidney lesions in TSC.
    DOI:  https://doi.org/10.64898/2026.09.22.753536
  7. bioRxiv. 2026 Sep 26. pii: 2026.09.25.754437. [Epub ahead of print]
    Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes.
    Mehdi Dianatpour, Dipanjan Banerjee, HyunKyung Kim, Jiyoung Moon, Rui Zhu, Hang Zhou, Arpita Neogi, Trojan Rugira, Shrikant Mane, Adebowale Adeniran, Brisa Paliuqi, Ho-Joon Lee, Lucila Ohno-Machado, Arya Mani.
      Residual cardiovascular risk persists despite lipid-lowering therapy, independent of LDL and Lp(a), reflecting cholesterol dysregulation. We identify STARD9, a lysosomal cholesterol-sensing kinesin, as a causal gene for divergent familial dyslipidemias and premature atherosclerosis. Its START domain binds cholesterol to govern lysosomal positioning. Rare variants segregate with autosomal dominant hypercholesterolemia and premature coronary disease, while common variants associate with reduced HDL and elevated triglycerides. Both converge on lysosomal cholesterol sequestration, ER depletion, mTORC1 SREBP2 activation, impaired autophagy, and NF-kB inflammation, yet diverge through opposite lysosomal positioning: the rare variant disperses lysosomes peripherally, phenocopying START domain loss across cholesterol sequestration, lysosomal positioning, and TFEB activation, triggering LDLR degradation and CASM/TFEB-dependent efflux that preserves HDL, whereas the common variant causes perinuclear retention that suppresses TFEB dependent lipid-handling transcripts, yielding hypertriglyceridemia and low HDL. In Stard9-knockout mice, enterocyte cholesterol sequestration drives SREBP2 dependent NPC1L1 upregulation and apical localization, increasing intestinal cholesterol absorption. These findings position lysosomal cholesterol trafficking as a targetable node in statin-refractory cardiovascular disease.
    DOI:  https://doi.org/10.64898/2026.09.25.754437
  8. FASEB J. 2026 Oct 15. 40(19): e72342
    Establishment of an Animal Model of Type 2 Cardiorenal Syndrome.
    Qian Liu, Xinting Wang, Peipei Cheng, Tianshu Yang, Chen Wang, Hua Zhou.
      Type 2 cardiorenal syndrome (CRS) is a complex clinical syndrome characterized by chronic kidney injury resulting from chronic cardiac dysfunction. Its underlying pathophysiological mechanisms remain incompletely understood, highlighting the urgent need for disease models that better mimic human pathology and accurately simulate the progression of cardiac-induced renal injury. Existing models possess significant limitations and often fail to adequately replicate the onset and progression observed in clinical Type 2 CRS patients. We therefore hypothesized that a double-hit approach combining left anterior descending (LAD) ligation (to induce acute myocardial infarction) with transverse aortic constriction (TAC) (to increase afterload) would produce a model that highly simulates the development and progression of clinical Type 2 CRS, characterized by heart failure and subsequent renal injury. A double-hit strategy combining LAD ligation and TAC was performed in mice to induce heart failure followed by secondary renal injury. At four post-operative time points (2 weeks, 4 weeks, 6 weeks, and 8 weeks), we assessed cardiac function, renal function, inflammatory damage, energy metabolism dysfunction, and renal/cardiac fibrosis. Proteomic analysis was additionally performed to characterize molecular changes and identify the optimal model configuration. At week 2, mice developed early-stage heart failure accompanied by mild kidney inflammation and abnormal energy metabolism. By week 4, these abnormalities progressed to marked inflammation, fibrosis, chronic heart failure, and overt kidney damage. The impairments in energy metabolism, inflammation, and fibrosis peaked at Weeks 6 and 8, leading to severe dysfunction of both the heart and kidneys. This double-hit model stably recapitulates the natural progression from chronic cardiac dysfunction to chronic kidney injury observed in Type 2 CRS. It therefore serves as a powerful and innovative research platform for in-depth exploration of the molecular mechanisms underlying Type 2 CRS, screening of potential therapeutic targets, and evaluation of novel interventional strategies.
    DOI:  https://doi.org/10.1096/fj.202601933R
  9. Signal Transduct Target Ther. 2026 Sep 29. pii: 414. [Epub ahead of print]11(1):
    Polymeric alpha-1 antitrypsin perturbs Paneth cell proteostasis and exacerbates intestinal inflammation.
    Francesco Annunziata, Felipe Dos Santos Matos, Irene Relvini, Jing Lu, Giovanna Federico, Claudia D'Agostino, Valentina Schiano, Veronica Maffia, Bruno Maria Custode, Gaetano Raiola, Barbara De Marino, Rossella De Cegli, Eugenio Del Prete, Elena Polishchuk, Carmen Ambrosio, Debora Compare, Gerardo Nardone, Francesco Neri, Nunzia Pastore.
      Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that protects tissue from neutrophil elastase and other proteases, particularly in the lung. Mutations in SERPINA1, including the Z mutation, lead to AAT deficiency (AATD), characterized by reduced circulating AAT and increased risk of pulmonary emphysema, liver cirrhosis, and hepatocellular carcinoma. Beyond these well-characterized manifestations, AATD has been associated with panniculitis, rheumatoid arthritis, and glomerulonephritis. Emerging evidence has also suggested a link between AATD and inflammatory bowel diseases (IBDs), although experimental validation is lacking. In this study, we demonstrate that PiZ transgenic mice expressing the polymer-forming ATZ display increased susceptibility to dextran sodium sulfate (DSS)-induced colitis, accompanied by marked Paneth cell abnormalities. The accumulation of polymeric ATZ in Paneth cells is associated with the endoplasmic reticulum (ER) stress response, impaired lysosomal clearance, altered association of Lysozyme-1 (Lyz1) with LC3-containing compartments, and increased Lyz1 secretion. These intestinal alterations were accompanied by changes in microbiota composition, whereas DSS exposure and exogenous lysozyme administration were associated with aggravated intestinal and hepatic pathology. Pharmacological inhibition of ER stress restored crypt homeostasis and normalized Lyz1 secretion. Human Pi*ZZ iPSC-derived intestinal organoids similarly showed ATZ polymer accumulation in secretory epithelial cells and transcriptional alterations involving ER protein processing and epithelial homeostasis. In addition, polymeric ATZ was detected in ileal crypts from a single individual with AATD and intestinal disease. Together, our data reveal a Paneth cell-intrinsic ER stress mechanism linking ATZ accumulation to gut epithelial dysfunction, highlighting a previously underexplored role of the gut-liver axis in AATD.
    DOI:  https://doi.org/10.1038/s41392-026-02925-9
  10. Neurobiol Dis. 2026 Sep 29. pii: S0969-9961(26)00378-5. [Epub ahead of print]230 107632
    deptor disruption induces axonal and behavioral abnormalities through altered cholesterol metabolism in zebrafish.
    Mingshan Zhou, Cuizhen Zhang, Gang Peng.
      The mechanistic target of rapamycin (mTOR) signaling pathway is a highly conserved regulator of cellular growth and survival. DEPTOR serves as an endogenous inhibitor of this pathway by directly binding to both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). While DEPTOR is extensively implicated in oncology and peripheral metabolism, its role in the nervous system remains poorly understood. In this study, we utilized CRISPR/Cas9 technology to disrupt deptor in the zebrafish model to investigate its neurodevelopmental functions. We found that deptor-/- larvae exhibit motor deficits alongside structural axonal abnormalities, characterized by misaligned and broadened axonal tracts. These phenotypes were accompanied by the transcriptional dysregulation of key cholesterol-regulatory genes and progressive, aberrant accumulation of cholesterol from 5 to 10 days post-fertilization. Pharmacological elevation of cholesterol levels recapitulated these axonal and behavioral defects in wild-type larvae, whereas clearance of excess cholesterol successfully rescued the mutant phenotype. Together, our findings demonstrate that deptor deficiency drives cholesterol dysregulation, causing structural and functional abnormalities in the nervous system. This study uncovers a novel link between DEPTOR, lipid homeostasis, and neurodevelopment, highlighting cholesterol metabolism as a potential therapeutic target for neurological disorders associated with mTOR pathway dysfunction.
    Keywords:  Axonal tract; Cholesterol; DEPTOR; SREBP-2; mTOR
    DOI:  https://doi.org/10.1016/j.nbd.2026.107632
  11. Sci Adv. 2026 Oct 02. 12(40): eaej6157
    S-Nitrosylation of glycogen phosphorylase regulates nuclear glycogenolysis and is impaired in metabolic liver disorders.
    Leandro R Soria, Alfonso M D'Alessio, Vincenzo Casertano, Elena Polishchuk, Andrea Pasquadibisceglie, Iolanda Boffa, Anna Diana, Rossella De Cegli, Lucia De Stefano, Edoardo Nusco, Paola Arena, Matteo Audano, Nico Mitro, Tsuyoshi Morita, Otto Baba, Antonietta Tarallo, Giancarlo Parenti, Sonam Gurung, Dany P Perocheau, Davide Selvestrel, Giovanni Sorrentino, Fabienne Rajas, Giuseppe Ronzitti, Andrés F Muro, Ayelet Erez, Karen Louise Thomsen, Pankaj K Singh, Charles John Arends, Maria Rita Braghini, Samira Safarikia, Joseph C Schindler, Julien Baruteau, Young Mok Lee, Anna Alisi, Marco Spada, Carlo Dionisi-Vici, Jonathan S Stamler, Matthew S Gentry, Nicola Brunetti-Pierri.
      Nuclear glycogen storage has been known for nearly 100 years. However, its role in diseases remains unclear. Here, we found nuclear glycogen storage in livers of mice and humans with argininosuccinic aciduria (ASA), an inborn error of metabolism. Nuclear glycogenolysis sustains histone acetylation and liver homeostasis. We show that hepatic nuclear glycogenolysis is regulated by nitric oxide (NO)-dependent control of the nuclear abundance of liver glycogen phosphorylase (PYGL), an enzyme involved in glycogen breakdown that translocates from the cytosol to the nucleus. In vivo, NO supplementation restored the nuclear content of PYGL by promoting its S-nitrosylation at cysteine-446 and its nuclear translocation. Next, we found that nuclear import of PYGL is mediated by HNRNPF, a regulator of RNA maturation that shuttles between the nucleus and cytosol, thus linking control of gene expression to RNA metabolism. Similar changes were detected in both rodent and human livers with metabolic dysfunction-associated steatotic liver disease (MASLD), a global health concern with limited therapies, that shares with ASA a decrease in NO synthesis. In conclusion, our findings reveal a mechanism underlying reduced glycogenolysis and hepatic nuclear glycogen storage disorders, a new group of metabolic disorders.
    DOI:  https://doi.org/10.1126/sciadv.aej6157
  12. Kidney360. 2026 Sep 28.
    The Polycystic Kidney Disease Cyst Transcriptome Defined by Integrating Spatial, Single Nuclear, and Bulk Transcriptomics.
    Muhammad Ibrahim Khan, Jielu Hao Robichaud, Humayra Afrin, Fouad T Chebib, Peter C Harris, Navin R Gupta.
       BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) has been transcriptionally profiled at single cellular resolution, yet dissociation eliminated cyst-defining morphology to preclude a retrograde analysis of the cyst transcriptome. Transcriptional profiling of dissected ADPKD cysts has demonstrated size-based transcriptional heterogeneity, impossible to define in prior single cell analysis, but sampling was neither single cell nor comprehensive to limit downstream transcriptional analysis.
    METHODS: 10X Genomics Visium spatial transcriptomics of an autosomal dominant polycystic kidney disease patient sample morphologically recognizes cysts to spatially characterize their ligand-receptor engagement, the signaling pathways of cystic transformation, and candidate cystic anchor genes that are specific and sensitive for cystic epithelia. Anchor gene validation in single nuclear RNA sequencing and cyst bulk RNA sequencing enhanced resolution, extended to cysts of variable size, and corroborated across ADPKD samples, prior to confirmatory confocal microscopy for protein-level localization.
    RESULTS: The polycystic kidney disease interactome may be enriched for vscular endothelial growth inhibitor-mediated hypoxia, fibrotic extracellular matrix, and proinflammatory transforming growth factor-β (TGF-β), tumor necrosis factor, and interferon-γ signaling. Enhanced ligand-receptor engagement between cysts and fibroblasts suggests Osteopontin and Macrophage migration inhibitory factor signals emanate from cysts and TWEAK, Tenascin-C, and Pleiotrophin signals into cysts. Cystic principal cells, standardized to non-cystic counterparts, implicates Hippo (YAP/TAZ), transforming growth factor-β (TGF-β/SMAD3), and mammalian target of rapamycin (mTORC2/SGK1) signaling in cystic transformation, while pathway analysis newly implicates nicotinic acetylcholine, cadherin, toll-like, and cholecystokinin receptor signaling. Top DEGs of cystic principal cells, interrogated for their specificity for cysts and their consistency across individual samples of single cell and cyst bulk RNA-seq, prioritizes musculin as a cystic anchor gene.
    CONCLUSIONS: Spatial transcriptomics morphologically and transcriptionally characterizes the polycystic kidney disease transcriptome. Ligand-receptor, pathway, and reactome analyses may provide clinically-relevant disease associations that inform mechanistic studies in animal and organoid models. Integrating spatial, single nuclear, and cyst bulk RNA-seq spatially recognizes cysts at single cell resolution, while accounting for size-based heterogeneity of cysts.
    DOI:  https://doi.org/10.34067/KID.0000001371
  13. Nat Commun. 2026 Oct 02. pii: 10130. [Epub ahead of print]17(1):
    Tonicity drives collecting duct maturation in the mammalian kidney.
    Daisuke Inoue, Koichiro Miike, Shunsuke Tanigawa, Kei-Ichiro Yasunaga, Rae Maeda, Tomoko Ohmori, Sayoko Fujimura, Masashi Mukoyama, Tomomi Kamba, Jose Aramburu, Cristina Lopez-Rodriguez, Yuki Sugiura, Yuichiro Izumi, Ryuichi Nishinakamura.
      Organ maturation is a fundamental biological process and a major challenge for organoid-based regenerative medicine. During kidney maturation, osmolality increases in the renal medulla for urine concentration, yet whether this extreme environment conversely contributes to kidney maturation remains unclear. Here we show that high tonicity, i.e., salt, drives morphological, transcriptional, and functional maturation of medullary collecting ducts (CDs) primarily via nuclear factor of activated T cells 5 (NFAT5). This occurs both in vitro and in vivo. Combining high tonicity with maturation-promoting hormones, we establish a robust maturation protocol for human medullary CD organoids and a functional assay to measure water permeability in CD organoids, enabling modeling of three disease states: NFAT5 deletion, and lithium-induced and congenital nephrogenic diabetes insipidus. Collectively, high tonicity drives mammalian kidney maturation, offering a promising platform to maximize the potential of organoids for future therapies.
    DOI:  https://doi.org/10.1038/s41467-026-77903-4
  14. Cell Rep. 2026 Oct 01. pii: S2211-1247(26)01144-7. [Epub ahead of print]45(10): 118065
    Lysosomal multi-omics reveals altered sphingolipid catabolism associated with lysosomal dysfunction in the aging brain.
    Chinmoy Sarkar, Yi Chen, Dexter Ph Nguyen, Mehari M Weldemariam, Yulemni Morel, Amir Mehrabani-Tabari, Nikki Gorny, Olivia Pettyjohn-Robin, Nivedita Hegdekar, Sagarina Thapa, Sazia Arefin Kachi, Sabrina Bustos, Stephanie Zalesak-Kravec, Christina Williams, Nicholas Leahy, Renee Ti Chou, Shilpa D Kumar, Carrie McCracken, Thomas A Blanpied, Mariusz Karbowski, Jace W Jones, Maureen A Kane, Michael P Cummings, Marta M Lipinski.
      Lipids dynamically reside in multiple intracellular locations, and their organellar distribution is important for function. During brain aging, lysosomal lipid changes have been noted, but lipid identity, interactions, and functional relevance have not been characterized. We used mass spectrometry to assess longitudinal changes in the lipidome and proteome of lysosomal fractions from the murine cortex, from 3 to 24 months, followed by multi-omics factor analysis (MOFA) to identify factors underlying lysosomal aging. Our data uncover an age-dependent increase in lysosomal abundance of lipid and protein myelin components and suggest altered sphingolipid catabolism favoring degradation of sphingomyelins over glycosphingolipids. We experimentally corroborate MOFA predictions to demonstrate that age-dependent accumulation of myelin-derived glycosphingolipids is associated with lysosomal enlargement and dysfunction and is most pronounced in microglia. Our findings suggest that age-related lysosomal lipidome changes resemble those observed in lysosomal storage diseases and underscore the importance of organelle-specific analyses for elucidating lipid function.
    Keywords:  CP: metabolism; CP: neuroscience; autophagy; brain aging; glycosphingolipids; lipid metabolism; lysosomes; mass spectrometry; microglia; multi-omics factor analysis (MOFA); myelin
    DOI:  https://doi.org/10.1016/j.celrep.2026.118065
  15. Mol Biomed. 2026 Sep 30. pii: 191. [Epub ahead of print]7(1):
    SGLT2 inhibitors: mechanisms, physiology and pharmacology, and clinical applications.
    Xue-Ting Zheng, Hui-Yi Xie, Xiu-Heng Wang, Yue Zhao, Jia-Yan Yang, Yun-Xi Liu, Xian-Liang Yuan, Hui-Fang Tang, Zhi-Sheng Jiang, Heng-Jing Hu.
      Sodium-glucose cotransporter 2 (SGLT2) is a low-affinity, high-capacity transporter expressed predominantly in the renal proximal tubule, where it mediates the sodium-coupled reabsorption of most filtered glucose. SGLT2 inhibitors have evolved from glucose-lowering agents into disease-modifying therapies across the cardio-renal-metabolic continuum. Blockade of proximal tubular transport induces glycosuria, osmotic diuresis, restoration of tubuloglomerular feedback, resetting of renal haemodynamics, and altered fluid compartmentalisation. These early renal and circulatory effects interact with systemic metabolic adaptations, including pseudo-starvation signalling, erythropoiesis, altered uric acid handling, and changes in substrate availability. At the cellular level, SGLT2 inhibition has been linked to improved ionic homeostasis and mitochondrial quality control, reduced oxidative stress, modulation of inflammation, and attenuation of maladaptive tissue remodelling. Endothelial injury may connect these cellular effects with microvascular dysfunction and fibrosis. Endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT) offer a mechanistic framework for understanding the relationship between microvascular injury and fibrosis. However, EndMT is best viewed as one component of a broader endothelial-stromal stress response rather than as a single proven mediator of clinical benefit. These pharmacodynamic and cellular effects help explain the consistent clinical efficacy of SGLT2 inhibitors across type 2 diabetes, chronic kidney disease, and heart failure (HF), while also informing emerging applications in acute HF, after myocardial infarction, and in patients with arrhythmia or metabolic dysfunction-associated steatohepatitis. This Review integrates mechanistic, pharmacological, and clinical evidence to identify unresolved translational gaps and future directions, including mechanism-informed biomarkers, imaging, spatial multi-omics, phenotype-guided patient stratification, dual sodium-glucose cotransporter 1/2 inhibition, and rational combination therapy.
    Keywords:  Cardio-renal-metabolic continuum; Chronic kidney disease; Endothelial-to-mesenchymal transition; Heart failure; Precision medicine; SGLT2 inhibitors
    DOI:  https://doi.org/10.1186/s43556-026-00604-3
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