Targeting the PRMT1 axis in cancer: from epigenetic plasticity to contextual therapeutic interventions

Context-dependent roles of DHX9 in Cancer: Molecular mechanisms, biomarker potential, and therapeutic perspectives.

DExH-box helicase 9 (DHX9) is a multifunctional nucleic acid helicase that participates in R-loop homeostasis, genome maintenance, RNA metabolism, and innate immune signaling. Accumulating evidence has linked aberrant DHX9 expression or activity to tumorigenesis, tumor progression, treatment response, and patient prognosis. However, its role in cancer is highly context-dependent, rather than uniformly oncogenic or tumor suppressive. Depending on its molecular partners, subcellular localization, post-translational modifications, tumor genotype, and immune microenvironment, DHX9 may either promote malignant phenotypes or contribute to tumor-restraining processes. In this review, we summarize the molecular characteristics and regulatory properties of DHX9, discuss its roles in genome stability, transcriptional and post-transcriptional control, circular RNA (circRNA) biogenesis, and tumor-immune crosstalk, and evaluate its emerging value as a potential biomarker and therapeutic target. We also highlight key challenges in this field, including mechanistic heterogeneity, insufficient translational validation, and the urgent need for context-informed patient stratification to maximize the clinical utility of DHX9-targeted strategies.

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

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.

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

An integrated overview of the molecular features and functional roles of BAP1 is provided, with particular emphasis on its impacts on the regulation of cell death including apoptosis, ferroptosis and disulfidptosis.

Decoding Context-Dependent Sirtuin Pharmacology in Cancer: Metabolic-Epigenetic Switches and Precision Therapeutic Targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Role of chromatin remodeling and immunopharmacology in cancer therapy.

Epigenetic modifications play a crucial role in cancer, influencing cellular physiology, extracellular matrix (ECM) remodeling, and immune responses. With growing emphasis on chromatin remodeling and the epigenetic regulation of immunity, these regulatory pathways and related players have become focal points of oncological investigations. Epigenetic manipulation of immune system components has emerged as a promising strategy in cancer treatment. Several FDA-approved "epi-drugs" target the epigenome to modulate immune responses and offer new opportunities across different cancers. DNA repair pathways contribute significantly to the avoidance of cancer initiation and also contribute to cellular resistance in cancer treatment. Chromatin remodelers such as INO80, Fun30, and RAD54 play essential roles in DNA damage response (DDR) through homologous recombination and non-homologous end-joining pathways, and their dysregulation leads to genome instability and tumor progression. Chromatin remodeling complexes, including SWI/SNF and CHD families, are frequently altered across various cancer types, further highlighting their role in cancer pathophysiology. Targeting these chromatin modifiers and associated DNA repair mechanisms may provide novel therapeutic options. In addition, combining epigenetic modulators with immunotherapies has shown promise in enhancing responses to immune checkpoint blockade. Epigenetic drugs such as histone deacetylase (HDAC) inhibitors and DNA methylation inhibitors are being explored for their synergistic effects with immunotherapy. While the interplay between chromatin remodeling, DNA repair, and immune responses provides a strong framework for developing targeted oncological strategies, further research is required to better understand these interactions and optimize their clinical application.

Protein arginine methyltransferases as regulators of phase separation: implications in cancer and neurodegenerative diseases.