Aug 2026· Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics· Vol 28 8, pp.
1025-1030
· 0 citations
Medicine
TL;DR
This review summarizes the core components and regulatory mechanisms of the Hippo pathway, describes its role in cardiac development, and elucidates the molecular mechanisms by which it contributes to ventricular septal defect, tetralogy of Fallot, and left ventricular noncompaction cardiomyopathy, aiming to provide a new theoretical basis for the early diagnosis and treatment of CHD.
The Hippo pathway is an evolutionarily conserved regulator of growth, regeneration, and organ homeostasis, and while its dysregulation is well established in cancer, the effects of inhibiting this pathway on normal tissues are less understood. Here we have systematically investigated the impact of Hippo pathway inhibition by comparing pharmacologic perturbation using a covalent small-molecule TEAD inhibitor (TEADi CMPD1, also known as GNE-8025) with genetic suppression of YAP/TAZ. We identified three key target organs that consistently emerged upon TEAD inhibition: the kidney, as well as the pancreas, and thymus. Across models, both perturbations led to comparable disease phenotypes in these organs, including tubular degeneration in the kidney, acinar atrophy in the pancreas, and lymphoid depletion in the thymus. However, the extent of damage was more pronounced in mice treated with the small-molecule inhibitor, highlighting potential dose and compound specific effects while remaining broadly consistent with the phenotypes observed upon genetic ablation of YAP/TAZ. This highlights the key role of evaluating both genetic and pharmacological perturbations to characterize the phenotypes and potential toxicities when modulating novel targets in oncology. To further investigate the mechanisms underlying pan-TEAD inhibition and kidney related adverse effects, we further characterized this class effect through a comprehensive transcriptomic analysis of the kidney to map the pathways involved in renal response. Significance Understanding on target toxicities is critical for the safe clinical development of TEAD inhibitors. Here, by integrating pharmacologic TEAD inhibition with genetic suppression by developing a mouse model that characterizes systemic, inducible knockdown of YAP/TAZ, we provide a systematic framework to define the Hippo pathway liabilities in vivo. We identify kidney, pancreas, and thymus as conserved target organs with concomitant phenotypes across both genetic and pharmacological methods, establishing these as pathway driven effects. Importantly, we uncover dose dependent and partially irreversible injury, particularly in kidney and pancreas, alongside mechanistic insight linking TEAD inhibition to aldosterone signaling disruption in kidney. These findings highlight the importance of strategies to identify monitorable, manageable adverse effect to guide clinical translation of TEAD targeting strategies.
Sayantanee Paul, Michelle Lepherd, Thijs J. Hagenbeek et al.· bioRxiv· 0 citations
Preclinical evidence suggests that KIF23 is a molecule with significant translational potential, demonstrating promising prospects in disease diagnosis, prognostic assessment, and targeted therapy, and further in-depth research on KIF23 will significantly advance precision medicine.
Yi Liu, Yu Luo, Pinghong Hu et al.· Cancer Cell International· 0 citations
Congenital heart diseases (CHDs) encompass a broad spectrum of structural anomalies with substantial clinical and genetic heterogeneity. They are the most common birth defects in humans, and a leading cause of paediatric morbidity and mortality. Yet, its genetic substrate remains difficult to interpret at the bedside: despite advances in cytogenetics and next-generation sequencing, a definitive or candidate genetic cause is identified in fewer than half of cases, and even when a variant is recovered, mapping it onto the developmental program that produces a specific malformation is rarely straightforward for the practising clinician. This narrative review revisits normal cardiogenesis as a single, coordinated developmental program, integrating embryological events with progenitor populations, transcription factor networks, and signalling pathways. We then highlight how perturbation of these developmental modules may result in syndromic and non-syndromic CHD. By aligning embryological events with their regulatory logic, the review offers a developmental framework intended to help clinicians situate molecular findings within the biology of heart formation, sharpen genotype–phenotype interpretation, support more precise diagnostic and prognostic reasoning, and inform emerging regenerative strategies for the malformed and injured heart.
Aline Saliba, J. Afiune, Aline Pic-Taylor et al.· Frontiers in Genetics· 0 citations
Summary Integral membrane protein 2A (ITM2A) is a type II transmembrane glycoprotein belonging to the BRICHOS superfamily. It primarily regulates organismal development and homeostasis and exhibits tumor-suppressive functions. Its expression is precisely regulated by a multidimensional network involving transcription factors, epigenetic modifications, and environmental signals. Within cellular signaling networks, ITM2A modulates multiple key pathways, including BMP, JAK/STAT, ERK, Hedgehog, and PKA-CREB. ITM2A is essential for the differentiation and functional maturation of various tissues, such as cartilage, bone, and muscle. Dysregulation of ITM2A function or expression is closely associated with malignancies, thyroid disorders, and acute transplant rejection. This review systematically summarizes the complex regulatory mechanisms of ITM2A in growth, development, and disease, with a particular focus on skeletal development and tumorigenesis, aiming to provide a theoretical basis for its potential use as a biomarker for development and disease diagnosis/treatment, as well as for the development of ITM2A-targeted therapeutics.
Xiaoling Deng, Yifang Wang, Lan Yang et al.· iScience· 0 citations
Cancer is the second leading cause of death on a global
scale and in 2022, approximately 20 million cases were
identified for the first time. 9.7 million deaths due to
cancer were reported as per the World Health
Organization (WHO) and the International Agency for
Research on Cancer (IARC). Cancer is a generic term
given for a large group of diseases, as it can affect any
part of the body. Several genetic and epigenetic
alterations take place in cancer cells so that they
deviate from normal metabolic processes. The
underlying mechanisms of mutations, metastasis,
migration and drug resistance highlight the urgent
need for understanding the signaling triggers and key
players involved in cancer pathogenesis. Mitogenactivated protein kinase (MAPK) is the most prevalent
signaling pathway that encompasses the RAS-RAFMEK-ERK signalling cascades. Kinases play a
substantial role in the pathway by activating
downstream targets. The MAPK pathway regulates
numerous processes such as the cell cycle, cell growth
and proliferation, cell differentiation, cell survival and
apoptosis.
Any dysregulation or alteration in such pathway could
lead to the development and progression of cancers
implicating resistance to apoptosis and resistance to
medical therapeutics such as chemotherapy and
radiotherapy. The potential role of altered MAPK
pathway in cancers has been inadequately understood.
The present review sheds light in understanding the
role of MAP kinases in the pathogenesis of cancer,
considering their prominence as the potential targets
for human cancer therapeutics.
Ramya Ramachandran, Shanmugam Kumaran· Research journal of biotechn...· 0 citations
The deltex (DTX) gene family encodes RING-type E3 ubiquitin ligases that are central to the regulation of the Notch signaling pathway, a mechanism governing cell fate, differentiation, proliferation, and apoptosis during development and adult tissue homeostasis. In Drosophila melanogaster, the Deltex (Dx) fine-tunes Notch signaling by modulating receptor endocytosis and degradation, acting as either an enhancer or a suppressor depending on the context. Insights from flies have revealed the evolutionary conservation of the Dx-Notch interaction across species, including humans. However, recent studies have expanded this view, identifying Dx as a regulator of multiple signaling pathways beyond Notch, specifically Wingless, Decapentaplegic, and Toll, underscoring its role as a hub for cellular communication. Through its broad regulatory network, Dx influences fundamental processes including cell growth, differentiation, apoptosis, and homeostasis. Dysregulation of Dx expression and function has been implicated in several diseases, ranging from cancer to immunological disorders and congenital abnormalities, positioning it as a promising therapeutic target. Despite these advances, important gaps remain in our understanding of Dx substrates, molecular mechanisms, and their full spectrum of physiological and pathological roles. Future research will be crucial to uncovering the broader biology of DTX family proteins and enabling their clinical application as diagnostic and prognostic markers. This review consolidates current knowledge and emerging insights on Dx, providing a framework to guide future research and therapeutic exploration.
Vartika Sharma, Pratikshya Sahoo, M. Mutsuddi et al.· Cellular and Molecular Life...· 0 citations
