bims-raghud 2026-11-01 papers

Issue of 2026–11–01
seven papers selected by
Irene Sambri, TIGEM

Trends Mol Med. 2026 Oct 26. pii: S1471-4914(26)00227-3. [Epub ahead of print]

Rethinking kidney cancer through the lens of microphthalmia (MiT)/transcription factor E (TFE) Biology.

Microphthalmia/transcription factor E (MiT/TFE) transcription factors are central regulators of lysosomal function, mechanistic target of rapamycin complex 1 (mTORC1) signaling, and cellular metabolism, and their dysregulation is increasingly recognized as a key driver of kidney cancer. This forum provides an overview of the molecular mechanisms underlying MiT/TFE-associated renal tumorigenesis and discusses their implications for cancer biology and therapy.

Keywords: FLCN–FNIP; TFE3; TFEB; kidney cancer

DOI: https://doi.org/10.1016/j.molmed.2026.09.011

Am J Surg Pathol. 2026 Oct 28.

Light Microscopy-Based Techniques to Identify TFEB-Altered Renal Cell Carcinoma: A Comparison Study With TFE3-Rearranged Renal Cell Carcinoma and Common Renal Cell Tumors.

Anna Caliò, Stefano Marletta, Cinzia Giacometti, Serena Pedron, Elena Bariani, Matteo Brunelli, Pietro Antonini, Lavinia Stefanizzi, Lisa Marcolini, Guido Martignoni.

TFEB‑altered renal cell carcinomas are rare neoplasms, frequently mimicking other tumors. Although FISH remains the diagnostic gold standard, its limited availability has prompted the evaluation of light microscopy‑based ancillary markers. This study compares the performance of immunohistochemistry and RNA‑ISH in detecting TFEB‑altered renal cell carcinomas and distinguishing them from other renal neoplasms. Sixteen FISH/molecularly confirmed TFEB‑altered renal cell carcinomas (12 rearranged, 4 amplified) were analyzed by immunohistochemistry for TFEB (3 different clones), cathepsin K (clone 3F9), and GPNMB, and RNA‑ISH for TRIM63 and TFEB. Forty-eight clear cell renal cell carcinomas, 48 papillary renal cell carcinomas, 72 chromophobe renal cell carcinomas, 48 oncocytomas, 5 TFE3‑rearranged renal cell carcinomas, and 4 FLCN/mTOR-mutated renal cell neoplasms served as controls. Staining patterns and diagnostic performance were assessed and compared. TFEB immunohistochemistry demonstrated variable sensitivity, with the Bethyl assay showing the greatest reliability. Cathepsin K (clone 3F9) and GPNMB displayed high sensitivity but lacked specificity, labeling 40% and 50% of TFE3‑rearranged tumors, respectively, and subsets of common renal neoplasms. Similarly, TRIM63 RNA‑ISH was strongly positive in all TFEB‑altered renal cell carcinomas but also in TFE3‑rearranged neoplasms. Instead, TFEB RNA‑ISH demonstrated exclusive expression in all TFEB‑altered renal cell carcinomas, with stronger signals in rearranged tumors, whereas it was negative in all control cases, including TFE3‑rearranged neoplasms. TFEB RNA‑ISH emerged as the most accurate light microscopy‑based method for detecting TFEB‑altered renal cell carcinomas, reliably distinguishing them from TFE3‑rearranged and other renal tumors, potentially representing a practical and cost‑effective alternative to FISH, particularly when molecular diagnostics are lacking.

Keywords: RNA in situ hybridization; TFEB-altered renal cell carcinoma; differential diagnosis; immunohistochemistry

DOI: https://doi.org/10.1097/PAS.0000000000002642

Cell Rep. 2026 Oct 26. pii: S2211-1247(26)01262-3. [Epub ahead of print]45(11): 118183

Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: Lessons from the Fabry heart.

Increasing evidence supports a pathogenic role for impaired energy metabolism in organ damage. Genetic diseases provide opportunities to investigate these mechanisms, as exemplified by Fabry disease (FD), caused by an α-galactosidase A (GLA) deficiency and globotriaosylceramide (Gb3) accumulation, with cardiomyopathy as the leading cause of death. Beyond Gb3 storage, impaired energy metabolism may contribute to cardiomyopathy. Here, we demonstrate mitochondrial dysfunction in FD heart and its therapeutic targeting. Using a humanized FD mouse model (R301Q-Tg/GLA knockout), embryonic fibroblasts, and neonatal and adult cardiomyocytes, we found impaired mitophagy and mitochondrial respiration, increased reactive oxygen species, and a vicious cycle aggravating lysosomal dysfunction. These defects progressed with age, causing accumulation of dysfunctional mitochondria, energetic failure, apoptosis, cardiac hypertrophy, and diastolic dysfunction. L-arginine, promoting NO/PGC-1α-dependent mitochondrial rescue, prevented cardiac abnormalities. Our findings identify mitochondrial dysfunction as a key driver of FD cardiomyopathy and reveal the lysosome-mitochondria axis as a targetable pathway in FD and beyond.

Keywords: CP: Cell biology; CP: Metabolism; Fabry disease; L-arginine; mitochondria; mitophagy

DOI: https://doi.org/10.1016/j.celrep.2026.118183

bioRxiv. 2026 Sep 02. pii: 2026.09.01.748694. [Epub ahead of print]

Hormetic heat shock activates HLH-30/TFEB independently of canonical nutrient-sensing pathways.

Tatiana M Moreno, Michelle E Brown, Caitlin M Lange, Gavin McLaren, Diego A Hernandez-Urbina, Cheng-Ju Kuo, Caroline Kumsta.

In Caenorhabditis elegans, a brief, sublethal heat shock (HS) induces a hormetic response that increases resistance to subsequent stress and extends lifespan. These benefits require hlh-30, the ortholog of mammalian transcription factor EB (TFEB). Although HS induces robust HLH-30 nuclear translocation, how this response is regulated remains poorly understood. Nutrient- and energy-sensing pathways, including mTORC1 and AMPK, regulate HLH-30/TFEB subcellular localization under other physiological conditions, but whether they mediate its nuclear translocation during HS is unknown. Here, we show that, although HS inhibited mTORC1 and dephosphorylated its conserved HLH-30 S201 target site, HLH-30 S201 phosphorylation was dispensable for HS-induced HLH-30 nuclear localization and hormetic protection. Moreover, HS remained protective in hlh-30 mutants when mTORC1 activity was reduced, revealing an HLH-30-independent component of the hormetic response. HS also activated AMPK and aak-2 was required for hormetic protection but dispensable for HS-induced HLH-30 nuclear localization and autophagosome formation. Together, these findings demonstrate that although HS engages canonical mTORC1 and AMPK signaling, these pathways do not account for HS-induced HLH-30 nuclear localization and instead make distinct contributions to hormetic protection. Our findings reveal stress-specific regulation of HLH-30/TFEB and point to additional mechanisms that drive its activation during heat stress.

DOI: https://doi.org/10.64898/2026.09.01.748694

Front Aging. 2026 ;7 1971981

Impaired autophagy and lysosome function in human fibroblast aging.

Juan José Unzueta-Mendoza, Ian García-Aguirre, Mina Königsberg, Isabel Arrieta-Cruz, Solangy Lizcano-Meneses, Jonathan J Magaña, Adriana Alarcón-Aguilar, Bulmaro Cisneros.

Background: Human aging is characterized by a progressive, time-dependent deterioration in physiological and cognitive functioning. Aging is driven by an array of interconnected cellular hallmarks, including genomic instability, mitochondrial dysfunction, telomere attrition, epigenetic alteration and dysfunctional autophagy. Autophagy is a cytoprotective (cellular degradation and recycling) pathway that maintains homeostasis during starvation or stress, and whose activity is associated with extended lifespan. This multi-step process comprises autophagosome formation and maturation, autophagosome-lysosome fusion, and cargo degradation. Thus, analysis of autophagy flux is necessary to precisely design therapeutic interventions aimed at restoring autophagy in aging.
Methods: The autophagy flux was comprehensively analyzed in human skin fibroblasts from donors of different ages (20-96 years old), a cell system that retains age-associated cellular and molecular signatures. The subcellular localization and activity of the master transcription factor of autophagy and lysosome biogenesis, TFEB, was analyzed by confocal microscopy assays and transcriptional expression of TFEB target genes (RT-qPCR) respectively. The autophagy flux was evaluated by monitoring the autophagy markers LC3 and p62 by Western blotting and confocal microscopy analyses, using inhibitor drugs to block autophagy or lysosomal activity. Autophagosome maturation and autophagosome-lysosome fusion were analyzed by colocalizing LC3 with Sintaxin-17 and LC3 with the lysosomal protein LAMP1 respectively, using inhibitor drugs and confocal microscopy assays. The analysis of lysosomal morphology and function was evaluated by lysobrite dye staining and live-cell confocal microscopy analysis.
Results: The initial stages of autophagy, including activation of TFEB, and autophagosome formation, remained apparently functional in fibroblast aging. In contrast, the rate of both autophagosome maturation and autophagosome-lysosome fusion, as well as the lysosomal function appears to be altered in aged fibroblasts. Specifically, enlarged dysfunctional lysosomes were identified as a hallmark of the fibroblasts of the 96-year-old donor. This lysosomal dysfunction may lead to a reduced ability to degrade canonical autophagy markers, LC3-II and p62, and the accumulation of lipofuscin.
Conclusion: Overall, the results provide evidence that autophagy flux is impaired at the late stages in aged fibroblasts, specifically in autophagosome maturation and autophagosome-lysosome fusion steps. Furthermore, it was demonstrated that this failure correlates with the presence of enlarged dysfunctional lysosomes. This study underscores the significance of enhancing lysosomal activity to counteract autophagy decline in aging.

Keywords: aging; autophagosomes; autophagy flux; fibroblast aging; lysosomes

DOI: https://doi.org/10.3389/fragi.2026.1971981

Acta Pharmacol Sin. 2026 Oct 30.

Transcription factor EB as a novel target for dimethyl fumarate to restore endothelial function in diabetes.

Lei He, Ri Min Tan, Leyi Wu, Qinghua Chen, Jinzhao Yang, Ziyu Han, Yang Zhang, Gang Fan, Yu Huang, Cheng-Lin Zhang.

Diabetes mellitus-associated endothelial dysfunction represents a pivotal early event in diabetic vasculopathy, linking metabolic derangements to vascular injury. Dimethyl fumarate (DMF), an FDA-approved drug for multiple sclerosis and psoriasis, exhibits potent anti-inflammatory and antioxidant properties, yet whether it protects against diabetic endothelial dysfunction and the underlying molecular mechanisms remain unclear. Here, diabetic db/db mice and the non-diabetic db/m+ littermates were treated with DMF (100 mg·kg-1·d-1) or vehicle for 4 weeks, and vascular function in aortic and mesenteric artery rings was assessed by wire myography. Human umbilical vein endothelial cells (HUVECs) and endothelial cell (EC)-specific Tfeb knockout (TfebECKO) mice were employed to investigate the target of DMF in vitro and in vivo. DMF restored the impaired endothelium-dependent relaxations (EDRs) in db/db mouse aortas and insulin-induced relaxations in mesenteric arteries, improved glucose tolerance, reduced aortic endothelial mitochondrial ROS (mito-ROS) accumulation, and lowered the expression of inflammatory markers. IL-1β induced phosphorylation and cytoplasmic retention of TFEB (indicative of TFEB inhibition), mito-ROS production, and inflammatory responses in HUVECs and mouse aortas, all of which were reversed by DMF pretreatment. These protective effects of DMF were largely reversed by TFEB knockdown in HUVECs or in aortas of TfebECKO mice. RNA sequencing data analysis revealed a substantial overlap between DMF-regulated and TFEB-overexpression transcriptional profiles, implicating a role of TFEB in DMF-induced suppression of inflammatory and oxidative pathways. Together, DMF ameliorates endothelial dysfunction in diabetes by inhibiting TFEB phosphorylation and restoring TFEB nuclear activity. Endothelial TFEB represents a critical mediator responsible for the vaso-protective effects of DMF and a promising therapeutic target for the treatment of diabetic vascular complications.

Keywords: diabetes; dimethyl fumarate; endothelial dysfunction; transcription factor EB; vascular inflammation

DOI: https://doi.org/10.1038/s41401-026-01944-0

Drug Des Devel Ther. 2026 ;20 648280

The Role and Mechanism of SGLT2 Inhibitors in Chronic Kidney Disease.

Jiaqian Xie, Yuqi Liu, Yi Zhao, Ying Wang, Tianbiao Zhou.

Chronic kidney disease (CKD) refers to structural or functional abnormalities of the kidneys caused by various factors lasting ≥3 months, or a decline in glomerular filtration rate (GFR) of <60 mL/min of unknown cause lasting ≥3 months. Its primary causes include diabetic kidney disease, hypertensive nephropathy, IgA nephropathy, membranous nephropathy, and lupus nephritis, among others. As a new class of antidiabetic drugs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown in numerous clinical studies and animal experiments to be effective in treating CKD of various etiologies. The renoprotective effects of SGLT2 inhibitors are independent of their glucose-lowering effects. Through mechanisms such as hemodynamics, oxidative stress, and anti-fibrosis, they reduce serum creatinine and urinary protein levels, thereby slowing the progression of CKD. This review primarily summarizes clinical and basic research on SGLT2i in the treatment of CKD and analyzes the signaling pathways through which SGLT2i exerts its effects on CKD. This demonstrates that SGLT2 inhibitors can delay the progression of kidney function decline and improve outcomes in patients across various subtypes through multiple mechanisms. They are suitable for patients with CKD of different etiologies and across different estimated glomerular filtration rate (eGFR) categories, indicating the significant potential and promising prospects for the widespread use of SGLT2 inhibitors in patients with CKD.

Keywords: SGLT2 inhibitors; chronic kidney disease; signaling pathways

DOI: https://doi.org/10.2147/DDDT.S648280