Aug 2026· Pathology, Research and Practice· Vol 287, pp.
156644
· 0 citations· 98 references
Medicine
TL;DR
This review provides 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.
Abstract
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.
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
Emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment and immunotherapy response, positioning it as an increasingly attractive target for intervention.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations
The tumor microenvironment (TME) is characterized by chronic inflammation, high metabolic activity, and aberrant vascular function, which together create an ecosystem that supports tumor progression. In this review, we summarize the multifaceted pro-tumorigenic mechanisms through which nicotinamide phosphoribosyltransferase (NAMPT) regulates key features of the TME, including macrophage polarization and immune responses, metabolic reprogramming and TME acidification, angiogenesis, and the maintenance of epithelial-mesenchymal transition and cancer stemness. These interconnected processes collectively shape TME evolution and promote malignant progression. We also integrate recent structural insights into NAMPT catalytic architecture and ligand-bound inhibitory and activating complexes, highlighting the structural basis for NAMPT druggability. We further discuss recent advances in therapeutic strategies targeting NAMPT in cancer, including natural products, small-molecule inhibitors, and RNA-based approaches, and we highlight current challenges and future directions in the field. A deeper understanding of the complex roles of NAMPT in the TME will be essential for shifting anticancer therapy from direct tumor cell killing toward systemic reprogramming of the tumor ecosystem.
CD44, a multifunctional transmembrane glycoprotein, is not only a bystander but also a crucial driver of cancer progression that promotes cancer stem cell maintenance, metastasis, and resistance to therapy. Therefore, CD44 is recognized as a promising therapeutic target in advanced malignancies. Here, we discuss its unique features, such as its structural diversity, which arise from alternative splicing and the post-translational modifications of cleavage and phosphorylation. In addition, we discuss the function of CD44 as a multivalent cell adhesion receptor for extracellular matrix components, including hyaluronic acid, fibronectin, osteopontin, and TSG6, thereby regulating lymphocyte activation, cell-cell interactions, cell adhesion, and migration within the extracellular matrix. Moreover, the emerging role of CD44 as a co-receptor of receptor tyrosine kinases such as epidermal growth factor receptor, c-MET, and vascular endothelial growth factor receptor 2 is highlighted to elucidate the contribution of CD44 to malignant signaling networks. We also discuss its potential as a therapeutic target in advanced cancers, particularly its applications in unconjugated antibodies, antibody-drug conjugates, peptide-based inhibitors, and chimeric antigen receptor-T cell therapies. We conclude by addressing the limitations observed in clinical studies and outlining promising opportunities for future development.
Hyun-Ji Oh, Seung-Tae Kim, Hyun-Jin Kim et al.· Experimental and Molecular M...· 0 citations
BACKGROUND
Tumor metastasis is the primary cause of cancer-related mortality. This complex process is orchestrated by the tumor microenvironment (TME) and metabolic reprogramming. Protein lactylation, a newly recognized post-translational modification derived from lactate metabolism, is emerging as a critical regulator of tumor progression and metastasis.
AIM OF REVIEW
This review aims to provide an overview of the current understanding of lactylation within the metastatic process and to offer an updated perspective on its regulatory role in tumor metastasis and its promise as a new therapeutic avenue.
KEY SCIENTIFIC CONCEPTS OF REVIEW
The review focuses on both the enzymatic and non-enzymatic mechanisms of lactylation and delineates the enzymatic machinery, including writers, erasers, and readers, that dynamically regulate this modification. It emphasizes how lactylation influences critical stages of metastasis, such as the epithelial-mesenchymal transition (EMT) and invasion, cancer stemness maintenance, immune evasion and TME remodeling, angiogenesis and vascular dissemination, and survival during colonization. Beyond these stage-specific roles, this review discusses how lactylation operates within a broader post-translational modification (PTM) network through crosstalk with acetylation, ubiquitination, and RNA methylation to amplify oncogenic signaling. Finally, the review evaluates emerging therapeutic strategies targeting lactate metabolism, the lactylation machinery, and site‑specific modifications, and addresses persistent challenges including context‑dependent functions, limited causal validation, and technical hurdles in isomer‑specific detection.
Xinyue Yu, Siwei Song, Yingji Ke et al.· Journal of Advanced Research· 0 citations
Cancer remains a major global health burden, with its incidence and mortality rates persistently high despite advances in treatment. Despite therapeutic innovations, malignant tumors continue to pose a formidable challenge to global health. Against this backdrop, the crosstalk between long non-coding RNAs (lncRNAs) and the Notch signaling pathway has emerged as a pivotal driver of tumorigenesis and progression. However, the complex regulatory network and a comprehensive mechanistic framework of this axis await systematic elucidation. This review systematically consolidates recent advances in understanding how lncRNAs precisely modulate Notch pathway activity through diverse mechanisms, including acting as competing endogenous RNAs, direct protein binding, epigenetic regulation, and exosome-mediated intercellular communication. The discussion encompasses various malignancies, spanning the digestive, respiratory, urogenital, nervous, and hematologic systems. The lncRNA-Notch regulatory axis is identified as a ubiquitous and functionally central oncogenic network. It orchestrates critical malignant phenotypes—such as such as stemness maintenance, epithelial-mesenchymal transition, metabolic shifts, drug resistance, and immune evasion—through intricate bidirectional crosstalk. Functional studies confirm that targeting key nodes of this axis can effectively reverse drug resistance and suppress tumor growth. Although challenges remain in its clinical translation, future research integrating single-cell multi-omics, nanotechnology, and other innovative strategies will undoubtedly open new avenues for precision diagnosis and cancer therapy.
Qing-miao Shi, Na Lou, Huiwu Xing et al.· Frontiers in Cell and Develo...· 0 citations