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.
The Hippo pathway prevents tissue overgrowth and tumorigenesis in many organs across species. Not surprisingly, this pathway limits the proliferation of progenitor cells in diverse regions of the nervous system, and its dysregulation can lead to neural tumors in humans. However, the functions of the Hippo pathway extend beyond proliferation control. Recent studies have revealed a remarkable functional diversity across neural lineages, encompassing morphogenesis, cell fate, tissue maintenance, and repair. This review synthesizes current evidence on the roles and regulation of the Hippo pathway in neural progenitor cells, glial cells, and neurons, highlighting context-dependent mechanisms and outstanding questions. With the core molecular machinery and many fundamental cellular functions of the Hippo pathway now established, the field is entering a new phase: unraveling the functional significance and regulatory complexity of Hippo signaling in physiologically relevant contexts-both normal and diseased-promises to deepen our mechanistic understanding of neural development and homeostasis, and unlock new strategies for tumor therapy and neural repair.
Xinwei Cao· Cold Spring Harbor Perspecti...· 0 citations
Kinesin family member 23 (KIF23), a key regulator of cell division, has attracted growing interest owing to its aberrant expression and functional dysregulation in numerous human diseases. However, its systematic mechanisms of action across various pathological types and its potential for clinical translation remain to be fully elucidated. This review integrates multidisciplinary literature and bioinformatics data to systematically summarize the molecular characteristics, regulatory networks, and core functions of KIF23 in various diseases. Accumulating evidence indicates that KIF23 is overexpressed in numerous malignant tumors, where it drives tumor proliferation, metastasis, and drug resistance by regulating cell cycle progression, the DNA damage response, metabolic reprogramming, and remodeling of the immune microenvironment. Its overexpression is strongly associated with poor prognoses. KIF23 also plays a significant role in various non-cancerous diseases, such as congenital dyserythropoietic anemia, pulmonary arterial hypertension, and neurocognitive disorders. Notably, it exhibits tumor-suppressive effects in specific contexts, including cervical cancer, highlighting its context-dependent function. Preclinical evidence indicates that targeting KIF23 effectively suppresses tumor progression and reverses drug resistance. In conclusion, preclinical evidence suggests that KIF23 is a molecule with significant translational potential, demonstrating promising prospects in disease diagnosis, prognostic assessment, and targeted therapy. Further in-depth research on KIF23 will significantly advance precision medicine.
Yi Liu, Yu Luo, Pinghong Hu et al.· Cancer Cell International· 0 citations
Summary KAT8 (MOF/MYST1) is a core histone acetyltransferase of the MYST family. Beyond its canonical H4K16ac activity, KAT8 catalyzes diverse acylations and regulates stem cell biology, DNA repair, metabolism, and immunity. This review systematically integrates KAT8’s regulatory networks across physiology and disease. We decipher the molecular basis of its context-dependent “double-edged sword” role in cancer, acting predominantly as an oncoprotein yet exhibiting tumor-suppressive functions under specific conditions. We evaluate current KAT8 inhibitor development, from early non-selective compounds to selective leads, and highlight persistent translational hurdles including insufficient specificity and limited in vivo efficacy. This work provides a comprehensive framework that clarifies recent controversies—such as whether H4K16ac primarily governs transcription or replication timing, and which KAT8-containing complex catalyzes, which acetylation mark—and establishes a rationale for future precision-targeting strategies and biomarker development grounded in KAT8 functional heterogeneity.
NEDD9 (Neural precursor cell expressed developmentally downregulated 9) is a scaffolding protein that plays a central role in coordinating multiple oncogenic signaling pathways involved in tumor progression. It regulates diverse cellular processes, including cell migration, epithelial-mesenchymal transition, stemness, and therapeutic resistance, primarily through its function as a signaling integrator. Despite increasing evidence supporting the importance of NEDD9 in cancer, several key challenges remain, including a lack of systems-level understanding of its regulatory networks, incomplete characterization of its role in tumor immune microenvironment modulation, and difficulties in developing effective therapeutic strategies targeting this scaffold protein. In this review, we provide a comprehensive and integrative analysis of NEDD9 by systematically linking its structural features, multilayered regulatory mechanisms, diverse biological functions, and clinical relevance within a unified conceptual framework. We further emphasize its role as a dynamic signaling hub in cancer progression. Finally, we highlight key research priorities, including the need for multi-omics integration, improved understanding of context-dependent functions, and the development of innovative strategies targeting NEDD9-associated signaling and interaction networks, which may facilitate its translation into clinical applications.
Yu Zhang, Lin Li, Ya Zhang et al.· Pathology, Research and Prac...· 0 citations
Abstract The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis and degradation. Its dysregulation is closely associated with various diseases, including cancer. S-phase kinase-associated protein 2 (SKP2) is a key E3 ubiquitin ligase component of the UPS. It induces proteasome-mediated protein degradation or modulates substrate function by conjugating K48-linked or K63-linked ubiquitin chains to diverse target proteins. Recent studies have shown that the overexpression of SKP2 in several cancer types is correlated with poor clinical outcomes, underscoring its potential as a therapeutic target. Notably, emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment (TME) and immunotherapy response, positioning it as an increasingly attractive target for intervention. In this review, the oncogenic properties of SKP2 and its underlying mechanisms were elucidated in multiple cancer types. Moreover, we systematically summarized future directions for SKP2-targeted therapy.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations