bims-raghud 2026-08-16 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–08–16
eight papers selected by
Irene Sambri, TIGEM

FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.
Established and emerging roles of lysosomal dysfunction in cardiac aging.
Pulmonary Manifestations of Birt-Hogg-Dubé Syndrome: A Single-Centre Retrospective Case Series of Seven Genetically Confirmed Patients.
Molecular Characterization of TSC1 and TSC2 Variants in a Greek Cohort of Tuberous Sclerosis Complex Patients.
Transcriptional and Epigenetic Regulation of Cell Fate by YAP and TAZ.
Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics.
Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.
Human iPSC-derived vascularized organoids: Strategy-based insights from 2D endothelial cells to 3D blood vessel organoids.

Autophagy Rep. 2026 ;5(1): 2705631

FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.

Halvor Ullern, Julie Aarmo Johannessen, Feyza Kasikci, Miriam Formica, Naghmeh Karimi Melve, Siri Andresen, Andreas Brech, Karol Axcrona, Kjersti Jørgensen, Lorant Farkas, Jorrit M Enserink, Helene Knævelsrud.

  Birt-Hogg-Dubé syndrome (BHD) is an autosomal, dominant condition caused by Folliculin (FLCN) mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under the situation of combined anabolic and catabolic activation. Using an established BHD patient-derived kidney cancer cell line, we confirmed that TFEB was permanently localized in the nucleus combined with an increase in canonical MTORC1 signaling, whereas bulk autophagy flux and LC3 lipidation were unaffected by FLCN status. However, we found that the autophagy receptor SQSTM1/p62 accumulated in enlarged puncta in the absence of FLCN. Finally, we recapitulate aberrant p62 accumulation in a Norwegian cohort of BHD kidney tumor samples. Our results demonstrate that FLCN loss is characterized by SQSTM1/p62 accumulation, although SQSTM1/p62 appears dispensable for anchorage-independent growth in cell models.

Keywords:  Autophagy; BHD; FLCN; SQSTM1/p62; renal cell carcinoma

DOI:  https://doi.org/10.1080/27694127.2026.2705631
Nat Cardiovasc Res. 2026 Aug;5(8): 675-692

Established and emerging roles of lysosomal dysfunction in cardiac aging.

Yohan Santin, Ilias Simon, Angelo Parini, Frank Lezoualc'h, Elena Sommariva.

Cardiac aging is a central biological process underlying most cardiovascular diseases. Lysosomes, once regarded as terminal degradative compartments, are now recognized as dynamic metabolic and signaling hubs whose dysfunction has profound consequences for the aging heart. Human lysosomal storage disorders provide compelling evidence that isolated lysosomal defects are sufficient to cause early cardiomyopathy, underscoring the myocardium's exceptional dependence on sustained lysosomal competence. In physiological aging, impaired autophagy is the most apparent manifestation of lysosomal decline but represents only one facet of a broader network regulating nutrient sensing, ion and lipid homeostasis, receptor trafficking, exocytosis/secretion and inter-organelle communication. Here, we review established and emerging lysosome-dependent mechanisms across the hallmarks of cardiac aging, highlighting lysosomes as potential upstream drivers of this process. We discuss key knowledge gaps and therapeutic strategies aimed at restoring lysosomal function, positioning lysosomes as central and actionable targets for preserving cardiac resilience with age.

DOI: https://doi.org/10.1038/s44161-026-00853-z
J Clin Med. 2026 Jul 25. pii: 5820. [Epub ahead of print]15(15):

Pulmonary Manifestations of Birt-Hogg-Dubé Syndrome: A Single-Centre Retrospective Case Series of Seven Genetically Confirmed Patients.

Anna Annunziata, Lidia Atripaldi, Roberto Rega, Anna Michela Gaeta, Mariano Mollica, Maurizia Lanza, Anna Perfetti, Valentina Di Spirito, Giuseppe Fiorentino.

  Background/Objectives: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline pathogenic variants in the folliculin (FLCN) gene. Although it carries a substantial lifetime risk of renal cell carcinoma, its earliest manifestations are typically pulmonary cysts and spontaneous pneumothorax, which are frequently misclassified as primary spontaneous pneumothorax, resulting in diagnostic delay and inadequate oncological surveillance. We aimed to characterise the real-world phenotypic spectrum of BHD encountered in a respiratory referral setting. Methods: We retrospectively describe seven consecutive patients with genetically confirmed BHD syndrome diagnosed at our tertiary referral centre between 2022 and 2024. Demographic data, smoking history, FLCN variants, pneumothorax episodes, high-resolution computed tomography (HRCT) findings, pulmonary function tests and extrapulmonary neoplasms were collected. Reporting followed the PROCESS 2020 guideline. Results: Mean age at genetic diagnosis was 53.1 years (range 41-64). All seven patients had multiple thin-walled pulmonary cysts on HRCT, with the typical basal, subpleural and paramediastinal distribution; three had a pneumothorax history. Despite largely preserved spirometry-mean forced expiratory volume in 1 s (FEV1) of 82.4% predicted-the diffusing capacity of the lung for carbon monoxide (DLCO) was reduced in five patients (mean of 67.4% predicted) and was the most frequently affected functional parameter, although the overall functional picture was heterogeneous. Five patients had solid neoplasms (one renal, one colorectal, one thyroid/parathyroid, one ovarian, one lung adenocarcinoma). Conclusions: In this referral-based case series, pulmonary cysts were a constant finding and DLCO was the most frequently reduced functional parameter, although the functional picture varied across patients. These descriptive observations are hypothesis-generating and require prospective, controlled validation-including comparison with other diffuse cystic lung diseases-before any diagnostic algorithm can be proposed.

Keywords:  Birt–Hogg–Dubé syndrome; FLCN; case series report; diagnostic delay; diffusing capacity; pulmonary cysts; rare disease; renal cell carcinoma; spontaneous pneumothorax

DOI:  https://doi.org/10.3390/jcm15155820
Hum Mutat. 2026 ;2026 4508699

Molecular Characterization of TSC1 and TSC2 Variants in a Greek Cohort of Tuberous Sclerosis Complex Patients.

Socratis N Avgeris, Florentia Fostira, Paraskevi Apostolou, Angeliki Delimitsou, Stefanos Smyrniotis, Drakoulis Yannoukakos, Dimitrios J Stravopodis, Popi Syntichaki, Gerassimos E Voutsinas.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem genetic disorder caused by pathogenic variants in the TSC1 or TSC2 genes, resulting in dysregulation of the mTOR signaling pathway and subsequent hamartoma formation. Although the genetic basis of TSC is well established, population-specific data on TSC1 and TSC2 variants are still emerging. The aim of this study was to characterize the variant spectrum of the TSC1 and TSC2 genes in a cohort of 34 unrelated probands from Greece, 26 of whom had a definite TSC diagnosis, whereas eight had a possible TSC diagnosis. Targeted next-generation sequencing (NGS) was performed to analyze all coding exons and flanking exon-intron boundaries of TSC1 and TSC2. Identified variants were subsequently validated by Sanger sequencing. Pathogenic or likely pathogenic variants were identified in 22 of 34 probands, corresponding to an overall diagnostic yield of 65% using the testing strategy applied in this study. Of these variants, 32% (7/22) occurred in TSC1 and 68% (15/22) in TSC2; seven variants (7/22; 32%) were previously unreported. The molecular detection rate was 77% (20/26) for patients meeting the criteria for definite clinical TSC diagnosis and 25% (2/8) for those with a possible TSC diagnosis. Exploratory genotype-phenotype analysis revealed a trend toward a more severe clinical presentation among patients harboring TSC2 variants. These findings expand the known molecular landscape of TSC and support the clinical utility of genetic testing for diagnosis, genetic counseling, and patient management.

DOI: https://doi.org/10.1155/humu/4508699
Cold Spring Harb Perspect Biol. 2026 Aug 10. pii: a041914. [Epub ahead of print]

Transcriptional and Epigenetic Regulation of Cell Fate by YAP and TAZ.

Ju-Gyeong Kang, Taejun Seol, Younghoon Kim, Dae-Sik Lim.

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (YAP/TAZ) are key transcriptional coregulators that govern mammalian cell fate through complex epigenetic mechanisms. As core effectors of the Hippo signaling pathway, they integrate diverse cellular signals-including those mechanical, metabolic, or biochemical in nature-to control lineage specification, organ development, and tissue homeostasis. Although they have been traditionally known for their roles in the control of organ size and tumorigenesis, more recent evidence has revealed their function as important epigenetic modulators that reshape chromatin landscapes to direct cell fate transitions across multiple tissue contexts. Through interactions with chromatin-modifying complexes, the transcriptional machinery, and lineage-specific factors, YAP/TAZ coordinate enhancer activation, superenhancer formation, and chromatin looping to establish transcriptional programs essential for cellular identity. This work reviews the current understanding of YAP/TAZ-mediated epigenetic regulation and examines their tissue-specific roles. We propose a unified mechanistic framework by which the level of YAP/TAZ activity determines enhancer landscapes that favor either differentiated or progenitor-like cellular states, providing a potential basis for applications to regenerative medicine and therapeutic interventions.

DOI: https://doi.org/10.1101/cshperspect.a041914
Nat Cardiovasc Res. 2026 Aug 10.

Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics.

Kaushik Amancherla, Angela M Taravella Oill, Xavier Bledsoe, Arianna L Williams, Nelson Chow, Anna J Smith, Melissa A Farrow, Shilin Zhao, Quanhu Sheng, David W Bearl, Alexander N Perez, Robert D Hoffman, Jonathan N Menachem, Hasan K Siddiqi, Douglas M Brinkley, Evan D Mee, Niran Hadad, Vineet Agrawal, Jeffrey Schmeckpepper, Aniket Rali, Stacy Tsai, Eric Farber-Eger, Quinn S Wells, Jane E Freedman, Nathan R Tucker, Jeffrey M Spraggins, Kelly H Schlendorf, Eric R Gamazon, Nicholas Banovich, Ravi V Shah.

Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current diagnostic approaches rely on histology, which exhibits wide diagnostic variability and lacks clinically relevant molecular phenotyping. Here we leverage image-based spatial transcriptomics at subcellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant recipients during and following histologically diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in immune and parenchymal cells across different classes of rejection. We observed broad overlap in transcriptional states across rejection severity and significant heterogeneity within rejection grades. Responders and nonresponders to augmented therapies had distinct transcriptomic profiles, with nonresponders exhibiting baseline T cell hyperactivation and tissue remodeling genes. We also identified cell-specific genes linked to long-term outcomes after heart transplant. These results underscore the importance of subtyping cellular states during rejection to stratify immune-cardiac interactions relevant to short- and long-term outcomes.

DOI: https://doi.org/10.1038/s44161-026-00849-9
Sci Adv. 2026 Aug 14. 12(33): eaee0509

Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.

Wenhao Zhao, Xudong Hu, Ruyi Wang, Han Zhang, Man Zhou, Hong Cao.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder primarily caused by mutations in the NPC1 gene. Most patients present with early-life symptoms including hepatosplenomegaly and digestive system impairment, followed by progressive neurodegeneration. However, effective therapeutic approaches to improve survival in NPC disease remain limited. In this study, using an npc1-knockout (NPC1-KO) zebrafish model established in our laboratory, our team suggests that npc1 deficiency appears to correlate with marked down-regulation of superoxide dismutase 2 (Sod2) expression, concurrent with excessive oxidative stress (OS), mitochondrial dysfunction, and defective mitophagy. Treatment with Mito-TEMPO, a mitochondria-targeted antioxidant acting on SOD, increased survival rates and ameliorated cholesterol accumulation and liver function impairment in early-stage NPC1-KO zebrafish. The underlying mechanism may involve attenuation of OS and promotion of PINK1/Parkin-dependent mitophagic flux through SOD2 enhancement. Our findings support Mito-TEMPO as a potential therapeutic agent and SOD2 as a possible target for NPC disease.

DOI: https://doi.org/10.1126/sciadv.aee0509
Biofabrication. 2026 Aug 04.

Human iPSC-derived vascularized organoids: Strategy-based insights from 2D endothelial cells to 3D blood vessel organoids.

Seo-Yeon Kong, Da-Hyun Kim.

  Organoids derived from human pluripotent stem cells (PSCs) have emerged as powerful in vitro models for studying development, disease, and therapeutic responses, yet their lack of functional vasculature limits growth, maturation, and physiological relevance. Early vascularization strategies relied on human umbilical vein endothelial cells, which lack organ-specific identity and introduce donor variability. The field is now undergoing a paradigm shift toward PSC-derived vasculature, which offers patient-specific, and developmentally stage-matched endothelium with PSC-derived organoids. This review summarizes current strategies for organoid vascularization, with emphasis on both human PSC-derived 2D endothelial cells (EC) and 3D blood vessels. Approaches relying on co-aggregation of differentiated ECs with organ-specific populations or external endothelial coating of pre-formed organoids. These improved survival and functional maturation but remain limited in spatial organization and perfusability. The advances have incorporated pre-formed vascular spheroids and iPSC-derived blood vessel organoids, which can be respectively fused with lineage-specific organoids to generate vascularized assembloids to enhance vascular architecture and tissue maturation. This review further highlights engineering the microenvironment to promote the formation of vascular niche, such as hypoxia modulation, transcriptional regulation, signaling transduction, and extracellular matrix engineering. In addition, we discuss the current limitations as well as future directions of vascularized organoids, including the unmet need for developing tissue-specific ECs, improved engraftment following transplantation, and organ-on-a-chip platforms. Collectively, integrating iPSC-derived vasculature within organoids provides a central framework toward physiologically relevant, perfusable tissues and expands the translational utility of organoid technologies for disease modeling and therapeutic development.

Keywords:  Blood vessel organoid; Disease modeling; Endothelial cells; Organoid; Vascularization

DOI:  https://doi.org/10.1088/1758-5090/ae94b5