bims-raghud 2025-04-20 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–04–20
eighteen papers selected by
Irene Sambri, TIGEM

Role of Extracellular Vesicles in TSC Renal Cystogenesis.
Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
Molecular landscape of clear cell renal cell carcinoma: targeting the Wnt/β-catenin signaling pathway.
TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma.
Autophagy, ER-phagy and ER dynamics during cell differentiation.
Splicing Analysis of Exonic TSC1 and TSC2 Gene Variants Causing Tuberous Sclerosis Complex.
Sirtuins and Resveratrol in Cardiorenal Diseases: A Narrative Review of Mechanisms and Therapeutic Potential.
Disrupted glucocorticoid receptor cell signalling causes a ciliogenesis defect in the fetal mouse renal tubule.
The role of autophagy in cancer: from molecular mechanism to therapeutic window.
The roles of the ubiquitin-proteasome system in renal disease.
Autophagy and Its Association with Macrophages in Clonal Hematopoiesis Leading to Atherosclerosis.
The multifaceted roles of the transcriptional coactivator TAZ in extravillous trophoblast development of the human placenta.
Cardiovascular therapeutic targets of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond heart failure.
Integration of Organoids With CRISPR Screens: A Narrative Review.
Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal.
Application of human cardiac organoids in cardiovascular disease research.
The effects of YAP/TAZ in cardiomyocytes: a scoping review.
Active control of mitochondrial network morphology by metabolism-driven redox state.

Int J Mol Sci. 2025 Mar 28. pii: 3154. [Epub ahead of print]26(7):

Role of Extracellular Vesicles in TSC Renal Cystogenesis.

Kamyar Zahedi, Mackenzie Morgan, Brenda Prieto, Marybeth Brooks, Tamara A Howard, Sharon Barone, John J Bissler, Christos Argyropoulos, Manoocher Soleimani.

  Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes and affects multiple organs. TSC proteins control cell growth by regulating the activity of the mechanistic target of rapamycin complex 1. Extracellular vesicles (EVs) are membrane-bound particles produced by cells that mediate cellular communication, function, and growth. Although extensive studies regarding the genetic basis of TSC exist, the exact mechanism contributing to its pathogenesis remains unresolved. It has been proposed that EVs generated by renal cyst epithelia of mice and cells with Tsc gene mutations contain factors that alter the function and proliferation of TSC-sufficient cells. To test this, EVs from the kidneys and kidney explants of wildtype and Tsc1KO mice were isolated and characterized by Western blotting, transmission electron microscopy, dynamic light scattering, and fluorescent nanoparticle tracking. Our results show an enrichment in EV-associated markers and particle sizes of similar ranges. RNA-seq and proteomic analyses identified EV shuttle factors. EV RNA and protein shuttle factors showed significant differences. Furthermore, EVs isolated from Tsc1KO mice inhibited the proliferation of M-1 cells. Understanding the role of EVs in cell proliferation and cystogenesis in TSC may lead to the development of new approaches for the treatment of this disease.

Keywords:  A-intercalated cells; collecting duct; cystogenesis; extracellular vesicles; kidney; principal cells; tuberous sclerosis complex

DOI:  https://doi.org/10.3390/ijms26073154
Sci Adv. 2025 Apr 18. 11(16): eads1842

Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.

Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.

Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.

DOI: https://doi.org/10.1126/sciadv.ads1842
Discov Oncol. 2025 Apr 14. 16(1): 524

Molecular landscape of clear cell renal cell carcinoma: targeting the Wnt/β-catenin signaling pathway.

Judyta Górka, Katarzyna Miękus.

  Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and is characterized by a complex molecular landscape driven by genetic and epigenetic alternations. Among the crucial signaling pathways implicated in ccRCC, the Wnt/β-catenin pathway plays a significant role in tumor progression and prognosis. This review delves into the molecular basis of ccRCC, highlighting the genetic and epigenetic modifications that contribute to its pathogenesis. We explore the significance of the Wnt/β-catenin pathway, focusing on its role in disease development, particularly the nuclear transport of β-catenin and its activation and downstream effects. Furthermore, we examine the role of antagonist genes in regulating this pathway within the context of ccRCC, providing insights into potential therapeutic targets. Dysregulation of this pathway, which is characterized by abnormal activation and nuclear translocation of β-catenin, plays a significant role in promoting tumor growth and metastasis. We explore the intricate molecular aspects of ccRCC, with a particular emphasis on this topic, underscoring the role of the pathway and emphasizing the importance and relevance of antagonist genes. Understanding the intricate interplay between these molecular mechanisms is crucial for developing innovative strategies to improve ccRCC treatment and patient outcomes.

Keywords:  Cancer; Kidney; Signaling pathways; Wnt pathway; ccRCC; β-catenin

DOI:  https://doi.org/10.1007/s12672-025-02228-5
Cell Rep. 2025 Apr 11. pii: S2211-1247(25)00310-9. [Epub ahead of print]44(4): 115539

TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma.

Choon Leng So, Ye Jin Lee, Bujamin H Vokshi, Wanlu Chen, Binglin Huang, Emily De Sousa, Yangzhenyu Gao, Marie Elena Portuallo, Sumaiya Begum, Kasturee Jagirdar, W Marston Linehan, Vito W Rebecca, Hongkai Ji, Eneda Toska, Danfeng Cai.

  Translocation renal cell carcinoma (tRCC) presents a significant clinical challenge due to its aggressiveness and limited treatment options. It is primarily driven by fusion oncoproteins (FOs), yet their role in oncogenesis is not fully understood. Here, we investigate TFE3 fusions in tRCC, focusing on NONO::TFE3 and SFPQ::TFE3. We demonstrate that TFE3 FOs form liquid-like condensates with increased transcriptional activity, localizing to TFE3 target genes and promoting cell proliferation and migration. The coiled-coil domains (CCDs) of NONO and SFPQ are essential for condensate formation, prolonging TFE3 FOs' chromatin binding time and enhancing transcription. Compared with wild-type TFE3, TFE3 FOs bind to new chromatin regions, alter chromatin accessibility, and form new enhancers and super-enhancers at pro-growth gene loci. Disruption of condensate formation via CCD modification abolishes these genome-wide changes. Altogether, our integrated analyses underscore the critical functions of TFE3 FO condensates in driving tumor cell growth, providing key insights for future therapeutic strategies.

Keywords:  CP: Cancer; CP: Molecular biology; TFE3 fusion; biomolecular condensates; cancer; chromatin accessibility; fusion oncoprotein; gene regulation; single-particle tracking; translocation renal cell carcinoma

DOI:  https://doi.org/10.1016/j.celrep.2025.115539
J Mol Biol. 2025 Apr 11. pii: S0022-2836(25)00217-7. [Epub ahead of print] 169151

Autophagy, ER-phagy and ER dynamics during cell differentiation.

Michele Cillo, Viviana Buonomo, Anna Vainshtein, Paolo Grumati.

  The endoplasmic reticulum (ER) is a multifunctional organelle essential for protein and lipid synthesis, ion transport and inter-organelle communication. It comprises a highly dynamic network of membranes that continuously reshape to support a wide range of cellular processes. During cellular differentiation, extensive remodelling of both ER architecture and its proteome is required to accommodate alterations in cell morphology and function. Autophagy, and ER-phagy in particular, plays a pivotal role in reshaping the ER, enabling cells to meet their evolving needs and adapt to developmental cues. Despite the ER's critical role in cellular differentiation, the mechanisms responsible for regulating its dynamics are not fully understood. Emerging evidence suggests that transcriptional and post-translational regulation play a role in fine-tuning ER-phagy and the unfolded protein response (UPR). This review explores the molecular basis of autophagy and ER-phagy, highlighting their role in ER remodelling during cellular differentiation. A deeper understanding of these processes could open new avenues for targeted therapeutic approaches in conditions where ER remodelling is impaired.

Keywords:  Cell Differentiation; Development; Endoplasmic Reticulum

DOI:  https://doi.org/10.1016/j.jmb.2025.169151
Hum Mutat. 2025 ;2025 1497712

Splicing Analysis of Exonic TSC1 and TSC2 Gene Variants Causing Tuberous Sclerosis Complex.

Qingqing You, Jingwei Liu, Ran Zhang, Zhi Wang, Bingying Zhang, Wencong Guo, Ning Xu, Irene Bottillo, Leping Shao.

  Tuberous sclerosis complex (TSC) is characterized by abnormalities in cell proliferation and migration, leading to the development of hamartomas, benign tumors, or malignant cancers, affecting both the skin and brain, as well as potentially impacting the heart, kidneys, lungs, and eyes, with varying patterns of involvement over a lifetime. It is primarily caused by mutations in the TSC1 and TSC2 genes. Aberrant splicing is a crucial factor in hereditary diseases. Alternative splicing is a key mechanism for expanding the diversity of the human proteome. Mutations disrupting canonical splice sites or splicing regulatory elements impede the utilization of splice sites, leading to exon skipping and intron retention. We comprehensively analyzed missense and nonsense mutations of TSC1 and TSC2 genes using bioinformatics tools and identified 10 candidate mutations affecting pre-mRNA splicing through minigene analysis. Mutations in TSC genes can lead to partial or complete exon skipping and/or intron retention through complex mechanisms. This study emphasizes the importance of evaluating their roles in the splicing of suspected pathogenic variants in TSC.

Keywords:  TSC; exon variants; minigene assay; splicing

DOI:  https://doi.org/10.1155/humu/1497712
Nutrients. 2025 Mar 30. pii: 1212. [Epub ahead of print]17(7):

Sirtuins and Resveratrol in Cardiorenal Diseases: A Narrative Review of Mechanisms and Therapeutic Potential.

Caterina Carollo, Alessandra Sorce, Emanuele Cirafici, Giuseppe Mulè, Gregorio Caimi.

  Aging is a very complex process, and it has been linked with Sirtuins. Sirtuin enzymes are a family of deacetylases that are related to caloric restriction and aging by modulating energy metabolism, genomic stability, and stress resistance. Up to now, seven sirtuins have been recognized. This narrative review aimed to analyze the literature produced between January 2005 and March 2025 to evaluate the role of sirtuins in chronic kidney disease and, as heart and kidney diseases are strictly interrelated, to explore their role in heart diseases and cardio-renal cross-talk. A reciprocal relationship between CKD and aging seems to exist since CKD may contribute to premature biological aging of different organ systems. SIRTs are involved in the pathophysiology of renal diseases; their activation can delay the progression of several renal diseases. Notably, an increasing number of studies linked SIRTs with different CVDs. SIRTs affect the production of mitochondrial reactive oxygen species (ROS) by modulating mitochondrial function. The imbalance of SIRT levels may increase the vulnerability to CVDs. SIRTs are involved in the pathophysiological mechanisms of HFpEF (heart failure with preserved ejection fraction) through different signaling pathways. Fibrosis is the linkage mechanism between the heart and kidney in the development of cardio-renal diseases. Current studies on sirtuins, resveratrol, and cardiorenal disease highlight their potential therapeutic benefits in regulating blood pressure, kidney function, lipid profiles, and inflammation, making them a promising area of investigation for improving cardiovascular and renal health outcomes. However, significant gaps remain. The limited availability of highly selective and potent sirtuin modulators hampers their clinical translation, as most existing compounds exhibit poor bioavailability and suboptimal pharmacokinetic properties.

Keywords:  CKD; CRS; CVD; SIRTs; aging; cardiorenal syndromes; resveratrol; sirtuins

DOI:  https://doi.org/10.3390/nu17071212
EMBO Rep. 2025 Apr 17.

Disrupted glucocorticoid receptor cell signalling causes a ciliogenesis defect in the fetal mouse renal tubule.

Kelly L Short, Jianshen Lao, Rachel Lam, Julie L M Moreau, Judy Ng, Mehran Piran, Alexander N Combes, Denny L Cottle, Timothy J Cole.

  Primary cilia are cell signalling and environment sensing organelles and have important roles during embryogenesis and homeostasis. We demonstrate glucocorticoid signalling is essential for normal cilia formation in mouse and human renal tubules. RNA sequencing of E18.5 kidneys from glucocorticoid receptor (GR) null mice identified significant reductions in key ciliogenesis-related genes including Ccp110, Cep97, Cep290 and Kif3a. Confocal microscopy reveals abnormal, stunted cilia on proximal tubules, podocytes, and collecting duct cells in mice with global or conditional deletion of GR. In contrast, activation of GR signalling with dexamethasone in human kidney organoids or mouse IMCD3 cells increases cilia length, an effect blocked by the GR antagonist RU486. Analysis of GR-null kidney extracts demonstrates reduced levels of pERK and SUFU identifying potential cell pathway crosstalk with GR signalling that coordinately regulate ciliogenesis in the renal tubule. Finally, dexamethasone reduces Aurora kinase A levels, a factor driving cilia disassembly and implicated in the pathogenesis of polycystic kidney disease.

Keywords:  Ciliogenesis; Ciliopathies; Glucocorticoid Receptor Signaling; Glucocorticoids; Kidney Development

DOI:  https://doi.org/10.1038/s44319-025-00454-0
Front Immunol. 2025 ;16 1528230

The role of autophagy in cancer: from molecular mechanism to therapeutic window.

Pooya Jalali, Arvin Shahmoradi, Amir Samii, Radman Mazloomnejad, Mohammad Reza Hatamnejad, Anwaar Saeed, Afshin Namdar, Zahra Salehi.

  Autophagy is a cellular degradation process that plays a crucial role in maintaining metabolic homeostasis under conditions of stress or nutrient deprivation. This process involves sequestering, breaking down, and recycling intracellular components such as proteins, organelles, and cytoplasmic materials. Autophagy also serves as a mechanism for eliminating pathogens and engulfing apoptotic cells. In the absence of stress, baseline autophagy activity is essential for degrading damaged cellular components and recycling nutrients to maintain cellular vitality. The relationship between autophagy and cancer is well-established; however, the biphasic nature of autophagy, acting as either a tumor growth inhibitor or promoter, has raised concerns regarding the regulation of tumorigenesis without inadvertently activating harmful aspects of autophagy. Consequently, elucidating the mechanisms by which autophagy contributes to cancer pathogenesis and the factors determining its pro- or anti-tumor effects is vital for devising effective therapeutic strategies. Furthermore, precision medicine approaches that tailor interventions to individual patients may enhance the efficacy of autophagy-related cancer treatments. To this end, interventions aimed at modulating the fate of tumor cells by controlling or inducing autophagy substrates necessitate meticulous monitoring of these mediators' functions within the tumor microenvironment to make informed decisions regarding their activation or inactivation. This review provides an updated perspective on the roles of autophagy in cancer, and discusses the potential challenges associated with autophagy-related cancer treatment. The article also highlights currently available strategies and identifies questions that require further investigation in the future.

Keywords:  autophagy; cancer; immunotherapy; precision-medicine; tumorigenesis

DOI:  https://doi.org/10.3389/fimmu.2025.1528230
Int J Med Sci. 2025 ;22(8): 1791-1810

The roles of the ubiquitin-proteasome system in renal disease.

Danqin Lu, Yingying Zhang, Ping Zhu, Jiao Wu, Cheng Yuan, Lihua Ni.

  The ubiquitin-proteasome system (UPS) is a major pathway of specific intracellular protein degradation through proteasome degradation of ubiquitin-labeled substrates. Numerous biological processes, including the cell cycle, transcription, translation, apoptosis, receptor activity, and intracellular signaling, are regulated by UPS. Alterations of the UPS, which render them more or less susceptible to degradation, are responsible for disorders of renal diseases. This review aims to summarize the mechanism of UPS in renal diseases. Besides, this review explores the relationship among UPS, autophagy, and deubiquitination in the development of renal disease. The specific molecular linkages among these systems and pathogenesis, on the other hand, are unknown and controversial. In addition, we briefly describe some anti-renal disease agents targeting UPS components. This review emphasizes UPS as a promising therapeutic modality for the treatment of kidney disease. Our work, though still basic and limited, could provide options to future potential therapeutic targets for renal diseases with a UPS underlying basis.

Keywords:  Ubiquitin-proteasome system; autophagy; deubiquitinases; diabetic kidney disease; renal disease

DOI:  https://doi.org/10.7150/ijms.107284
Int J Mol Sci. 2025 Apr 01. pii: 3252. [Epub ahead of print]26(7):

Autophagy and Its Association with Macrophages in Clonal Hematopoiesis Leading to Atherosclerosis.

Shuanhu Li, Xin Zhou, Qinchun Duan, Shukun Niu, Pengquan Li, Yihan Feng, Ye Zhang, Xuehong Xu, Shou-Ping Gong, Huiling Cao.

  Atherosclerosis, a chronic inflammatory disease characterized by lipid accumulation and immune cell infiltration, is linked to plaque formation and cardiovascular events. While traditionally associated with lipid metabolism and endothelial dysfunction, recent research highlights the roles of autophagy and clonal hematopoiesis (CH) in its pathogenesis. Autophagy, a cellular process crucial for degrading damaged components, regulates macrophage homeostasis and inflammation, both of which are pivotal in atherosclerosis. In macrophages, autophagy influences lipid metabolism, cytokine regulation, and oxidative stress, helping to prevent plaque instability. Defective autophagy exacerbates inflammation, impairs cholesterol efflux, and accelerates disease progression. Additionally, autophagic processes in endothelial cells and smooth muscle cells further contribute to atherosclerotic pathology. Recent studies also emphasize the interplay between autophagy and CH, wherein somatic mutations in genes like TET2, JAK2, and DNMT3A drive immune cell expansion and enhance inflammatory responses in atherosclerotic plaques. These mutations modify macrophage function, intensifying the inflammatory environment and accelerating atherosclerosis. Chaperone-mediated autophagy (CMA), a selective form of autophagy, also plays a critical role in regulating macrophage inflammation by degrading pro-inflammatory cytokines and oxidized low-density lipoprotein (ox-LDL). Impaired CMA activity leads to the accumulation of these substrates, activating the NLRP3 inflammasome and worsening inflammation. Preclinical studies suggest that pharmacologically activating CMA may mitigate atherosclerosis progression. In animal models, reduced CMA activity accelerates plaque instability and increases inflammation. This review highlights the importance of autophagic regulation in macrophages, focusing on its role in inflammation, plaque formation, and the contributions of CH. Building upon current advances, we propose a hypothesis in which autophagy, programmed cell death, and clonal hematopoiesis form a critical intrinsic axis that modulates the fundamental functions of macrophages, playing a complex role in the development of atherosclerosis. Understanding these mechanisms offers potential therapeutic strategies targeting autophagy and inflammation to reduce the burden of atherosclerotic cardiovascular disease.

Keywords:  atherosclerosis; chaperone-mediated autophagy (CMA); clonal hematopoiesis (CH); inflammatory; macrophage; programmed cell death

DOI:  https://doi.org/10.3390/ijms26073252
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2426385122

The multifaceted roles of the transcriptional coactivator TAZ in extravillous trophoblast development of the human placenta.

Gudrun Meinhardt, Hanna Waldhäusl, Andreas I Lackner, Jasmin Wächter, Theresa Maxian, Anna-Lena Höbler, Sigrid Vondra, Victoria Kunihs, Leila Saleh, Peter Haslinger, Peter Kiraly, Andras Szilagyi, Nandor G Than, Jürgen Pollheimer, Sandra Haider, Martin Knöfler.

  Insights into the molecular processes that drive early development of the human placenta is crucial for our understanding of pregnancy complications such as preeclampsia and fetal growth restriction, since defects in maturation of its epithelial cell, the trophoblast, have been detected in the severe forms of these diseases. However, key regulators specifying the differentiated trophoblast subtypes of the placenta are only slowly emerging. By using diverse trophoblast cell models, we herein show that the transcriptional coactivator of HIPPO signaling, TAZ, plays a pivotal role in the development of invasive extravillous trophoblasts (EVTs), cells that are essential for decidual vessel remodeling and adaption of maternal blood flow to the placenta. Ribonucleic acid sequencing (RNA-seq) or protein analyses upon TAZ gene silencing or CRISPR-Cas9-mediated knockout in differentiating trophoblast stem cells, organoids, primary EVTs, choriocarcinoma cells, or villous explant cultures unraveled that the coactivator promoted expression of genes associated with EVT identity, motility, and survival. Accordingly, depletion or chemical inhibition of TAZ, interacting with TEA domain family member 1 (TEAD1), impaired EVT differentiation, invasion, and migration and triggered apoptosis in the different trophoblast models. Notably, the coactivator also suppressed cell cycle genes and regulators of trophoblast self-renewal and prevented EVTs from cell fusion in organoids and primary cultures. Moreover, TAZ promoted human leukocyte antigen G (HLA-G) surface expression and increased NUAK1 kinase in EVTs thereby maintaining its own expression. In summary, the transcriptional coactivator TAZ plays a multifaceted role in the development of the EVT cell lineage by controlling different biological processes that initiate and preserve differentiation.

Keywords:  TAZ; differentiation; extravillous trophoblast; human placenta; trophoblast organoid

DOI:  https://doi.org/10.1073/pnas.2426385122
Pharmacol Ther. 2025 Apr 15. pii: S0163-7258(25)00073-7. [Epub ahead of print] 108861

Cardiovascular therapeutic targets of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond heart failure.

Matteo Armillotta, Francesco Angeli, Pasquale Paolisso, Marta Belmonte, Emanuel Raschi, Guido Di Dalmazi, Sara Amicone, Lisa Canton, Damiano Fedele, Nicole Suma, Alberto Foà, Luca Bergamaschi, Carmine Pizzi.

  Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease. This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.

Keywords:  Acute coronary syndrome; Arrhythmias; Cardiomyopathies; Chronic coronary syndrome; Chronic kidney disease; SGLT2 inhibitors; Valvular heart disease

DOI:  https://doi.org/10.1016/j.pharmthera.2025.108861
Biol Cell. 2025 Apr;117(4): e70006

Integration of Organoids With CRISPR Screens: A Narrative Review.

Rushikesh Mukhare, Khushboo A Gandhi, Anushree Kadam, Aishwarya Raja, Ankita Singh, Mrudula Madhav, Rohan Chaubal, Shwetali Pandey, Sudeep Gupta.

  Organoids represent a significant advancement in disease modeling, demonstrated by their capacity to mimic the physiological/pathological structure and functional characteristics of the native tissue. Recently CRISPR/Cas9 technology has emerged as a powerful tool in combination with organoids for the development of novel therapies in preclinical settings. This review explores the current literature on applications of pooled CRISPR screening in organoids and the emerging role of these models in understanding cancer. We highlight the evolution of genome-wide CRISPR gRNA library screens in organoids, noting their increasing adoption in the field over the past decade. Noteworthy studies utilizing these screens to investigate oncogenic vulnerabilities and developmental pathways in various organoid systems are discussed. Despite the promise organoids hold, challenges such as standardization, reproducibility, and the complexity of data interpretation remain. The review also addresses the ideas of assessing tumor organoids (tumoroids) against established cancer hallmarks and the potential of studying intercellular cooperation within these models. Ultimately, we propose that organoids, particularly when personalized for patient-specific applications, could revolutionize drug screening and therapeutic approaches, minimizing the reliance on traditional animal models and enhancing the precision of clinical interventions.

Keywords:  clustered regularly interspaced short palindromic repeats (CRISPR); libraries; neoplasms; organoid; personalized medicine; screening

DOI:  https://doi.org/10.1111/boc.70006
Hum Mutat. 2023 ;2023 4899372

Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal.

Hannah D West, Mark Nellist, Rutger W W Brouwer, Mirjam C G N van den Hout-van Vroonhoven, Luiz Gustavo Dufner de Almeida, Femke Hendriks, Peter Elfferich, Meera Raja, Peter Giles, Rosa M Alfano, Angela Peron, Yves Sznajer, Liesbeth De Waele, Anna Jansen, Marije Koopmans, Anneke Kievit, Laura S Farach, Hope Northrup, Julian R Sampson, Laura E Thomas, Wilfred F J van IJcken.

Tuberous sclerosis complex (TSC) is caused by inactivating variants in TSC1 and TSC2. Somatic mosaicism, as well as the size and complexity of the TSC1 and TSC2 loci, makes variant identification challenging. Indeed, in some individuals with a clinical diagnosis of TSC, diagnostic testing fails to identify an inactivating variant. To improve TSC1 and TSC2 variant detection, we screened the TSC1 and TSC2 genomic regions using targeted HaloPlex custom capture and next-generation sequencing (NGS) in genomic DNA isolated from peripheral blood of individuals with definite, possible or suspected TSC in whom no disease-associated variant had been identified by previous diagnostic genetic testing. We obtained >95% target region coverage at a read depth of 20 and >50% coverage at a read depth of 300 and identified inactivating TSC1 or TSC2 variants in 83/155 individuals (54%); 65/113 (58%) with clinically definite TSC and 18/42 (43%) with possible or suspected TSC. These included 19 individuals with deep intronic variants and 54 likely cases of mosaicism (variant allele frequency 1-28%; median 7%). In 13 cases (8%), we identified a variant of uncertain significance (VUS). Targeted genomic NGS of TSC1 and TSC2 increases the yield of inactivating variants found in individuals with suspected TSC.

DOI: https://doi.org/10.1155/2023/4899372
Front Cell Dev Biol. 2025 ;13 1564889

Application of human cardiac organoids in cardiovascular disease research.

Hongyan Zhang, Peng Qu, Jun Liu, Panke Cheng, Qian Lei.

  With the progression of cardiovascular disease (CVD) treatment technologies, conventional animal models face limitations in clinical translation due to interspecies variations. Recently, human cardiac organoids (hCOs) have emerged as an innovative platform for CVD research. This review provides a comprehensive overview of the definition, characteristics, classifications, application and development of hCOs. Furthermore, this review examines the application of hCOs in models of myocardial infarction, heart failure, arrhythmias, and congenital heart diseases, highlighting their significance in replicating disease mechanisms and pathophysiological processes. It also explores their potential utility in drug screening and the development of therapeutic strategies. Although challenges persist regarding technical complexity and the standardization of models, the integration of multi-omics and artificial intelligence (AI) technologies offers a promising avenue for the clinical translation of hCOs.

Keywords:  cardiovascular disease; clinical translation; disease models; drug screening; human cardiac organoids

DOI:  https://doi.org/10.3389/fcell.2025.1564889
Mol Biol Rep. 2025 Apr 15. 52(1): 392

The effects of YAP/TAZ in cardiomyocytes: a scoping review.

Yenni Limyati, Ardo Sanjaya, Ray Sebastian, Julia Windi Gunadi, Diana Krisanti Jasaputra, Vitriana Biben, Ronny Lesmana.

  The Hippo signaling pathway, through its effectors' yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), plays a pivotal role in heart development, regeneration, and repair. Despite the well-recognized role of YAP in promoting cardiomyocyte proliferation and differentiation, the underlying mechanisms require further explanation. Therefore, this scoping review was conducted to explore the underlying mechanisms of YAP and TAZ in cardiomyocyte biology. In this scoping review, 138 studies were screened using PRISMA extension for scoping reviews guidelines to examine the upstream regulators, mechanisms, and therapeutic potential of YAP/TAZ in cardiomyocytes. Articles were selected based on relevance to YAP/TAZ signaling in cardiac regeneration and focused on upstream regulators, signaling pathways, and therapeutic applications. Data were extracted using standardized forms, and thematic analysis was performed iteratively. YAP activation regulated several processes, including cardiomyocyte proliferation, differentiation, and protection against oxidative stress. Mechanotransduction factors influence YAP activity, linking the biomechanical environment to cardiac regeneration. Novel upstream regulators, such as prorenin receptors, melatonin, and ERBB2, were identified as YAP/TAZ modulators. Moreover, downstream pathways such as Wnt/β-catenin, PI3K/Akt, and TLR-mediated inflammation confer their effects on cellular proliferation, mitochondrial dynamics, and inflammation. Several therapeutic targets involving YAP that could enhance cardiac regeneration while reducing fibrosis and inflammation were identified. However, significant research gaps remain, including the underexplored role of TAZ, necessity for in vivo studies and transcriptomics to elucidate cell-specific effects, and intricate regulatory networks of YAP/TAZ.

Keywords:  Cardiomyocytes; Myocardial injury; Myocardial regeneration; Transcriptional coactivator with PDZ-binding motif; Yes-associated protein

DOI:  https://doi.org/10.1007/s11033-025-10492-5
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2421953122

Active control of mitochondrial network morphology by metabolism-driven redox state.

Gaurav Singh, Vineeth Vengayil, Aayushee Khanna, Swagata Adhikary, Sunil Laxman.

  Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)-through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.

Keywords:  electron transport chain; mitochondrial network; reactive oxygen species; redox state

DOI:  https://doi.org/10.1073/pnas.2421953122