KAT8-mediated epigenetic modifications: Physiological functions, heterogeneity in disease, and advances in targeted development

The context-dependent duality of MEG3: a pivotal regulator and promising target in inflammation-associated diseases.

SKP2 in Cancer: From Molecular Regulation to Therapeutic Vulnerabilities and Translational Perspectives

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.

The functions, mechanisms and clinical relevance of RNA and protein acetyltransferase NAT10: a comprehensive review.

The rapid advances in epigenetic and epitranscriptomic regulatory mechanisms have opened new prospects for precision therapies in various diseases. N-acetyltransferase 10 (NAT10) is currently the only known eukaryotic RNA ac4C acetyltransferase and has also been reported to acetylate multiple protein substrates, regulating diverse physiological processes. In this review, we comprehensively describe the domain organization, structural features and subcellular localization of NAT10. The molecular mechanisms underlying NAT10-mediated RNA ac4C modification and protein acetylation, as well as their biological functions across physiological and pathological contexts, are systematically summarized, with the aim of facilitating its clinical translation. Furthermore, we review the recent advances in NAT10-targeted therapeutic strategies, discuss the potential for combining NAT10-targeted strategies with existing treatment modalities, and propose possible approaches for optimization. By integrating current evidence, this review provides insights into the functions of NAT10 and highlights future research directions for its validation and translational development as a clinical therapeutic target in various diseases.

Tumor suppressor BAP1 emerges as a key regulator of metabolism and cell death in tumors

BRCA1-associated protein 1 (BAP1) is a deubiquitinase (DUB) localized in both the nucleus and cytoplasm and is widely recognized as a tumor suppressor. Germline and somatic alterations in BAP1 have been strongly associated with increased susceptibility to diverse cancer types and with adverse clinical outcomes. Although BAP1 is best known for its role in epigenetic regulation, particularly through the modulation of histone H2A monoubiquitination (H2Aub) and gene transcription, accumulating evidence suggests that its functional repertoire extends well beyond these canonical activities. BAP1 is increasingly viewed as a central molecular hub through which fundamental cellular processes are integrated and coordinated via its catalytic activity and dynamic protein interaction networks. In this review, the pleiotropic functions of BAP1 are systematically examined across several biological dimensions, including epigenetic regulation, genomic stability, cellular metabolism, and cell fate determination. Notably, BAP1-mediated regulation is highly context dependent, as cell type, differentiation status and tumor microenvironmental (TME) cues may shape its downstream effects and contribute to heterogeneous biological outcomes. By synthesizing these multidimensional regulatory mechanisms, this review provides an integrated overview of the molecular features and functional roles of BAP1, with particular emphasis on its impacts on the regulation of cell death including apoptosis, ferroptosis and disulfidptosis. Collectively, these insights underscore the evolving understanding of BAP1 biology over the past decade and highlight the need for renewed attention to this critical tumor suppressor and its therapeutic potential in cancer.

Substrate-selective mTORC1 regulation and gene dosage–dependent tissue divergence in Birt–Hogg–Dubé syndrome

Birt-Hogg-Dubé (BHD) syndrome, caused by mutations in the tumor suppressor gene FLCN, has traditionally been classified as a classic “mTORopathy” characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC/D to govern substrate-selective mTORC1 regulation. Synthesizing emerging evidence, we describe an integrated pathogenic framework: biallelic FLCN inactivation drives renal tumorigenesis via constitutive MiT/TFE nuclear accumulation and metabolic reprogramming, whereas haploinsufficiency suffices to disrupt structural integrity in the lung and skin. By reconciling the “mTORC1 paradox” through the lens of gene dosage and temporal signaling dynamics, we highlight novel therapeutic vulnerabilities targeting MiT/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.

The lncRNA-m6A axis in cancer: a bidirectional regulatory network in tumor progression and therapeutic resistance.

BACKGROUND Long non-coding RNAs and N6-methyladenosine RNA methylation represent two pivotal layers of gene regulation. Their extensive crosstalk forms a sophisticated bidirectional network that is fundamentally rewired in cancer. MAIN BODY This review synthesizes current knowledge to elucidate the principles and consequences of this synergistic axis. We detail how m6A modification dictates long non-coding RNA stability, splicing, localization, and function through recruitment of distinct "reader" proteins, with one "reader" family primarily mediating decay while another promotes stabilization. Conversely, we examine how long non-coding RNAs act as scaffolds, guides, and decoys to modulate the activity and specificity of the m6A machinery, establishing powerful feedforward and feedback loops. This reciprocal regulation converges on multiple cancer hallmarks, including proliferation, metabolic reprogramming, immune evasion, stemness, and therapeutic resistance. We critically discuss experimental strategies to establish causal relationships, including site-directed mutagenesis, CRISPR-based editing, and rescue assays. We also evaluate current methodological limitations in m6A detection, from antibody-dependent approaches to emerging nanopore sequencing, and highlight how single-cell and spatial transcriptomic technologies can resolve cell-state-specific networks within the tumor microenvironment. From a translational perspective, we compare small molecule inhibitors targeting m6A "writers" with RNA-based therapies, addressing their respective delivery challenges and toxicity concerns. Finally, we outline how m6A-related long non-coding RNA signatures serve as prognostic biomarkers and liquid biopsy tools for non-invasive cancer monitoring. CONCLUSION By integrating molecular mechanisms with clinical perspectives, this review charts a roadmap for targeting the epitranscriptomic-long non-coding RNA circuit in precision oncology.