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Background/Objectives: PHF6 is a chromatin-binding protein located in the nucleus, and it is involved in transcriptional regulation. However, limited research exists on the specific roles and mechanisms of PHF6 across various tumors. Methods: Based on The Cancer Genome Atlas (TCGA) database, we analyzed PHF6 expression in pan-cancer. We first evaluated the relevance between PHF6 and prognosis; then, the relevance between PHF6 and immune cell infiltration in pan-cancer were analyzed. Subsequently, we explored the correlation between PHF6 and cancer heterogeneity, such as tumor mutation burden (TMB) and microsatellite instability (MSI), as well as cancer stemness. Finally, the role of PHF6 was validated in liver cancer and pancreatic cancer cell lines by cell proliferation assays. Results: PHF6 expression was higher in the vast majority of cancers than their normal counterparts. PHF6 was substantially correlated with prognosis and immune cell infiltration in various cancers. Moreover, PHF6 expression showed a strong correlation with cancer heterogeneity and stemness in certain cancer types. Additionally, the depletion of PHF6 inhibited cell proliferation in both liver and pancreatic cancer cells. Conclusions: PHF6 expression was closely associated with the occurrence and development of many types of cancer, and it might promote cancer progression by inhibiting the function of the immune microenvironment, while knockout of PHF6 significantly inhibited the tumor cells proliferation.

Background: The MYC pathway is highly activated in gastric cancer (GC), but the MYC oncogene’s structural biology makes direct pharmacological inhibition very difficult. We hypothesized that BRD4, as a major co-activator of MYC, maintains MYC-dependent survival circuits, thus making BRD4 a key therapeutic vulnerability in late GC. Methods: We carried out a comprehensive transcriptomic analysis by utilizing large-scale data sets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), then these computational forecasts were later verified in strict clinical cohorts via molecular and histological methods. Functional verification was done through genetic and pharmacological interference by means of CRISPR-Cas9 gene deletion and PROTAC-induced protein breakdown with ARV771, ultimately, the therapeutic efficacy and systemic safety of these interventions were assessed in vivo with mouse xenograft models. Results: Our analyses revealed that the expression of BRD4 was significantly increased in GC tissues and there was a strong connection between this increase and the MYC hyperactivation, advanced TNM staging, and shortened patient survival. Our knockout (KO) experiments found that the viability of tumor cells depended greatly on the BRD4 - MYC - BCL2 signaling pathway because when BRD4 was depleted, the expression of BCL2, a crucial anti-apoptotic protein, decreased substantially. When pharmacological intervention was applied using ARV771, these cancer-related characteristics were effectively reversed, resulting in the suppression of tumor proliferation, the decrease of BCL2 levels, and significant inhibition of the growth of xenograft tumors in vivo without observable toxicity. Conclusion: Our findings suggest that BRD4 acts a chief epigenetic controller which promotes the progress of GC by intensifying MYC-dependent survival and ARV771 blocks this survival advantage, thus presenting a highly compelling rationale for integrating BRD4 degraders into modern targeted regimens.

Forkhead box K1 (FOXK1) is an important member of the FOX transcription factor family and functions as a signal-responsive regulator of cellular metabolism, proliferation, differentiation, and stress adaptation. FOXK1 activity is tightly controlled by a multilayered regulatory network, including genetic and epigenetic alterations, transcriptional regulation, non-coding RNAs, and diverse post-translational modifications. These regulatory networks collectively coordinate FOXK1 stability, subcellular localization, and transcriptional activity in a context-dependent manner. Disruption of this tightly balanced regulatory system can lead to sustained FOXK1 activation and contribute to disease pathogenesis.In cancer, FOXK1 predominantly functions as an oncogenic transcription factor that promotes metabolic reprogramming, maintenance of cancer stem cell properties, epithelial-mesenchymal transition, invasion, metastasis, vasculogenic mimicry, and therapeutic resistance. Beyond oncology, emerging evidence further implicates FOXK1 in metabolic disorders, inflammatory diseases, reproductive dysfunction, and neurological conditions, suggesting broader context-dependent pathological functions. Given its central role in multiple disease-associated signaling networks, FOXK1 has emerged as a potential therapeutic target. In this review, we systematically summarize the structural characteristics and regulatory mechanisms of FOXK1, and comprehensively discuss its roles in physiological and pathological processes. We further highlight current advances in FOXK1-targeted therapeutic strategies and address the key challenges for clinical translation. This review provides a conceptual framework for future therapeutic strategies and rational drug development targeting FOXK1.

Background and Objective: Lung cancer ranks among the most prevalent malignancies globally. Despite progress in early detection and standard therapies lowering overall mortality, there remains an urgent demand for optimized combinatorial regimens, reliable biomarkers and individualized strategies to advance precision lung cancer care. Epigenetic-targeted agents, represented by DNA methylation and histone lysine deacetylase (HDAC) inhibitors, have exhibited encouraging anti-tumor effects, and the Food and Drug Administration (FDA)-approved EZH2 inhibitor tazemetostat has further validated the translational value of epigenetic therapy across multiple tumors. This narrative review systematically summarizes epigenetic alterations and corresponding targeted inhibitors in lung cancer, and clarifies the clinical prospects of epigenetic tools for diagnostic biomarker development and stratified precision treatment. Methods: We searched PubMed and Web of Science Core Collection from database inception to January 31, 2026 with keywords covering lung cancer, DNA methylation, histone modification and epigenetic targeted therapy. Only full-text English original articles and reviews were retained. Key Content and Findings: This review systematically characterizes aberrant epigenetic signatures in lung cancer, encompassing DNA methylation, histone methylation, and the recently discovered histone lactylation, while detailing epigenetic biomarkers applicable to diagnosis and targeted therapy. We further summarize subtype-specific research advances of KMT/KDM, HDAC, EZH2 and LSD1 inhibitors in distinct lung cancer subtypes, with core functions including suppressing tumor proliferation, modulating neuroendocrine phenotypic transition, reversing therapeutic resistance, and amplifying anti-tumor immune responses. Conclusions: Dysregulated epigenetic modifications serve as core drivers of lung cancer progression, and various epigenetic small-molecule inhibitors possess broad application potential for lung cancer precision treatment. Combined regimens integrating epigenetic agents with immunotherapy or chemotherapy can strengthen anti-tumor responses, yet subtype heterogeneity and unsatisfactory clinical efficacy of some targeted drugs remain major obstacles. The accumulated preclinical and clinical epigenetic evidence summarized herein provides solid theoretical support for developing novel diagnostic biomarkers and individualized stratified therapeutic strategies against lung cancer.

Common cancers share germline susceptibility, yet the genetic architecture of a truly pan-cancer component of carcinogenesis remains incompletely resolved. We applied genomic structural equation modelling (gSEM) to genome-wide association studies (GWAS) summary statistics for 12 cancers (>600,000 European-ancestry cases) to separate a latent pan-cancer genetic factor from cancer-specific components, and then performed a multivariate GWAS of that factor. We conducted comprehensive downstream genetic, predictive, and functional analyses to characterise the resulting pan-cancer factor. We identified 133 LD-independent loci associated with the pan-cancer factor, including eight loci not previously associated with any cancer phenotype. Pan-cancer genetic risk was concentrated in evolutionarily conserved regulatory DNA, with enrichment in promoter and enhancer annotations and tissue-relevant signals in mammary and uterine contexts. A pan-cancer polygenic risk score (PRS) derived from the latent-factor GWAS improved prediction of overall cancer in UK Biobank (Royston-Sauerbrei R² = 2.97%), showed significant predictive value for most assessed cancers (R² up to 8.66%), and retained predictive signal in an independent East Asian validation dataset (Nagelkerke R² = 0.56%), outperforming a previous meta-analysis-based cross-cancer PRS and all site-specific PRSs. Gene and pathway prioritisation identified 132 putative risk genes across 106 loci, including 21 genes with little or no prior cancer annotation, and implicated canonical genome maintenance and cell cycle programmes alongside less emphasised processes involving organelle organisation, vesicle trafficking, and protein post-translational modification. Finally, proteome-wide Mendelian randomisation identified 23 blood proteins with putative causal effects on pan-cancer risk, including six druggable targets. Together, these results delineate a gSEM-derived pan-cancer genetic architecture, provide a cross-site PRS for overall cancer susceptibility, and nominate genes and circulating proteins for functional follow-up and prevention-oriented target discovery. Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, and National Key Research and Development Program of China.