Drug therapy serves a key role in the treatment of cervical cancer, which is one of the most common types of solid tumor in female patients. Therefore, it is important to seek more effective and less toxic therapies. Protein arginine methyltransferase 5 (PRMT5) is a key oncogenic target in cervical cancer, providing a rational basis for the development of targeted therapeutic agents. MS4322 is a highly selective proteolysis targeting chimera degrader specifically targeting PRMT5. Therefore, the present study aimed to investigate the therapeutic potential of MS4322 against cervical cancer and the underlying molecular mechanisms. The effects of MS4322 on human cervical HeLa cells were investigated by Cell Counting Kit‑8, clone formation, wound healing and Transwell assay, flow cytometry, immunofluorescence staining, immunohistochemistry and small interfering RNA assay. PRMT5 expression was upregulated in cervical cancer tissue, and functional analyses confirmed that PRMT5 promoted the proliferation of cervical cancer cells. MS4322 significantly decreased PRMT5 mRNA expression, as well as the proliferation, migration, invasion and clone formation ability of HeLa cells, leading to cell cycle arrest in G0/G1 phase and inducing apoptosis. Mechanistically, MS4322 downregulated the expression of PRMT5, β‑catenin, Wnt‑3a, and c‑myc, while upregulating GSK‑3β, thereby inactivating the Wnt/β‑catenin pathway. These findings indicated that MS4322 exerted anti‑tumor effects via regulating the PRMT5/Wnt/β‑catenin pathway and may serve as a promising candidate agent for cervical cancer treatment.

Covalently closed circular DNA (cccDNA) represents the central obstacle to achieving a functional cure for chronic hepatitis B virus (HBV) infection. Poly6, a peptide encoded within the HBV genome, was investigated for antiviral efficacy in hepatocyte-derived cell lines, hydrodynamic injection models, and HBV transgenic mice. Poly6 administration markedly decreased cccDNA, pregenomic RNA, and viral DNA without detectable cytotoxicity. Poly6 also showed synergistic antiviral effects with entecavir. Mechanistic analyzes demonstrated that Poly6 initiates parallel upstream events: mitochondrial stress resulting in oxidized mtDNA release and activation of the STING-IRF3 pathway, and induction of IFI16, a nuclear DNA sensor implicated in interferon regulation. Both signals converged on robust type I interferon (IFN-I) production. The IFN-I response subsequently promoted expression of canonical ISGs, including iNOS, which generated nitric oxide to disrupt nucleocapsid assembly. Concurrently, IFI16, whose abundance was further increased by interferon signaling, amplified IFN-I production and imposed epigenetic silencing of cccDNA through Sp1 sequestration and histone hypoacetylation. Chromatin immunoprecipitation confirmed reduced acetylation of H3K27, H4K5, and H4K12 on cccDNA minichromosomes. These results delineate a unified IFN-I-centered cascade in which Poly6 coordinates complementary antiviral activities, supporting its translational potential as a therapeutic candidate for durable HBV control.

The tumor suppressor protein p53 orchestrates cellular responses to stress by regulating the transcription of target genes involved in processes such as cell cycle control, DNA damage repair and apoptosis. The protein kinase DYRK1B, known to promote cancer cell survival and contribute to DNA damage repair, is overexpressed in various tumor types. Here, we demonstrate that expression of DYRK1B - but not its closely related paralog DYRK1A - is upregulated by cytostatic drugs (Actinomycin D, Doxorubicin) in multiple cancer cell lines. This induction required functional p53 and was mediated by p53-dependent activation of the transcription factor RFX7. Furthermore, we show that DYRK1B physically interacts with RFX7 and counteracts its activation by p53, thereby establishing a negative feedback loop that attenuates RFX7-dependent gene expression. This inhibitory effect of DYRK1B was strictly dependent on its catalytic activity and could be blocked by using small-molecule DYRK1 inhibitors. In conclusion, our study identifies DYRK1B as an indirect p53 target that suppresses p53-mediated activation of RFX7. These findings suggest that pharmacological inhibition of DYRK1B may represent a therapeutic strategy to enhance RFX7 tumor suppressor function.

Cancer progression involves coordinated regulation of oncogenes and tumor suppressors. This study explores the interplay of ENOX2 (ecto-NADH oxidase disulfide-thiol exchanger 2), MMP2 (matrix metalloproteinase-2), and regulatory genes Ras Association Domain Family Member 1, Isoform A (RASSF1A), WAP Four-Disulfide Core Domain Protein 10A (WFDC10A), and Methyltransferase-Like Protein 7A (METTL7A) across multiple cancer cell lines, and evaluates the anticancer potential of repurposed mebendazole.

The degradation of overexpressed proteins has emerged as a promising strategy for halting disease progression, particularly in cancer. Traditional small-molecule drugs often face limitations in the elimination of pathogenic proteins, leading to the development of targeted protein degradation (TPD) approaches. A prominent strategy for TPD is the proteolysis targeting chimaera (PROTAC) which harnesses the ubiquitin proteasome system, the cell's innate degradation machinery, to degrade proteins of interest (POIs). In this review, we will focus on the design and synthetic strategies that led the advancements of PROTACs as a cancer therapy for the targeted degradation of poly ADP-ribose polymerases (PARPs), glutathione peroxidase 4 (GPX4) and epigenetic regulators. We also aim to address the prevailing challenges in PROTAC development and clinical translation, namely target diversification, oral bioavailability, stability, degradation efficiency, and optimising multivalent binding.

Myo-inositol (MI) reduces hepatic histone acetylation in the enhancer-promoter regions of Elovl6 (ELOVL fatty acid elongase 6) in high-fructose diet (HFD)-fed rats. We examined whether dietary MI supplementation altered the epigenetic modifications in the transcribed regions of Fasn (fatty acid synthase) and Elovl6 in fatty livers of HFD-fed rats. MI supplementation alleviated HFD-induced hepatic expression of Fasn and Elovl6 probably by decreasing the acetylation of histones H3 and H4, and binding of cyclin-dependent kinase 9 and RNA polymerase II in the transcribed regions of these genes. Therefore, dietary MI supplementation can alleviate fatty liver disease by altering epigenetic modifications.

Acute myeloid leukemia (AML) remains challenging to treat due to extensive genetic heterogeneity, high relapse rates, and treatment-related toxicity. Although drug combinations offer therapeutic promise, their selection is often empirical. Here, we introduce Combinatorial Proteome Integral Solubility/Stability Alteration analysis (CoPISA), a high-throughput proteomics workflow that captures protein solubility/stability alterations uniquely induced by drug combinations. We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. We uncovered an emergent mechanism termed "conjunctional targeting", in which combinatorial drug action induces combination-exclusive protein targets consistent with an AND-gate logic model. LS-specific converged on SUMOylation, chromatin condensation, and VEGF-linked adhesion, while RU-specific targets disrupted DNA-damage checkpoints, mitochondrial bioenergetics, and RNA-splicing. Post-translational modification analysis revealed combination-induced acetylation, methylation, and phosphorylation of key AML proteins, including NPM1. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.

Yixiao formula (YXF), a traditional Chinese herbal medicine, has demonstrated clinical efficacy in alleviating symptoms of diabetic cardiomyopathy (DCM). The therapeutic mechanism underlying YXF's effects on DCM remains poorly understood. Myocardial fibrosis is a key pathogenic mechanism in DCM, and previous studies have indicated that miR-133a may be involved in its progression. Given that the TGF-β/Smads signaling pathway is a well-established mediator of myocardial fibrosis, investigating the mechanistic role of YXF through miR-133a and the TGF-β/Smads pathway warrants further exploration.

The rising prevalence of chronic diseases, including cancer, metabolic disorders, neurodegenerative, and cardiovascular conditions, presents a growing challenge to modern medicine and public health.

Sarcopenia is highly prevalent in individuals with diabetes and is associated with impaired physical function and increased mortality. Diabetes-associated skeletal muscle atrophy is driven by chronic inflammation, dysregulated anabolic-catabolic signaling, and activation of ubiquitin-proteasome-mediated protein degradation. Emerging evidence suggests that histone deacetylases (HDACs) act as epigenetic regulators of metabolic and inflammatory pathways; however, their role in diabetic sarcopenia remains incompletely understood.

The WRKY transcription factor is a key regulatory protein involved in defence hormone signalling and plays a pivotal role in plant hormone-mediated disease resistance. However, the specific mechanism by which WRKY transcription factors regulate the jasmonic acid (JA) pathway to confer resistance against Verticillium wilt in cotton remains poorly understood. In this study, we demonstrated that GbWRKY11 expression in Gossypium barbadense was induced by both Verticillium dahliae and methyl jasmonate (MeJA), and its encoded protein functioned as a nuclear transcription activator. Functional analyses revealed that GbWRKY11 enhances Verticillium wilt resistance by modulating JA pathway-related gene expression in both cotton and Arabidopsis. Exogenous MeJA application restored resistance in GbWRKY11-silenced plants, further supporting its role in JA-mediated immunity. Mechanistically, GbWRKY11 directly binds to the W-box motif in the promoter of GbLOX5, a key JA biosynthesis gene, and activates its transcription. Silencing GbLOX5 compromised cotton resistance to Verticillium wilt, confirming the importance of JA synthesis in this defence response. Our findings elucidate the molecular mechanism by which GbWRKY11 mediates immune responses against Verticillium wilt, providing novel insights into the genetic resources associated with disease resistance in G. barbadense.

Staphylococcus aureus biofilm formation enhances survival on host tissues and medical devices. This study tested how oxidative stress (H₂O₂), pH (5-9), NaCl (0-10%), and human serum (5-50%) affect the Newman strain biofilm and key genes (icaA, icaD, sarA). Biofilm was quantified by crystal violet assays and Lowry protein assay methods, and gene expression was measured by quantitative real-time PCR. Biofilm biomass was quantified using crystal violet staining and Lowry protein assays under various environmental conditions. Statistical significance was determined using ANOVA with post hoc analysis (p < 0.001). Hydrogen peroxide induced a dose-dependent reduction in biomass, with significant repression of icaA, icaD, and sarA expression at 3% H₂O₂ (≤ 22.8%, p < 0.001). Similarly, deviations from neutral pH markedly impaired biofilm formation, with acidic (pH 5) and alkaline (pH 9) conditions reducing biomass by 34.6% and 41.7%, respectively, accompanied by strong downregulation of biofilm-associated genes (p < 0.001). In contrast, NaCl exerted a biphasic effect: mild osmotic stress (1.25% and 5%) enhanced biofilm biomass (up to 154.2%) in the case of crystal violet assays and at 5% biomass increased to 130.8 ± 10.8*%; at 10%, it was 103.5 ± 6.1% (no significant change) in the case of protein quantification, and gene expression (icaA 160.55%, icaD 168.18%, sarA 149.8%, p < 0.001), whereas higher concentrations (≥ 10%) restored expression to near-control levels. Serum exposure produced a threshold-dependent response, with low concentrations (5-10%) slightly enhancing gene expression (~ 110%), while higher concentrations (20-50%) significantly repressed both biomass and transcription, with profound inhibition found at 50% (icaA 12.94%, icaD 10.88%, sarA 12.79%, p < 0.001). In addition, confocal laser scanning microscopy technique is used as a confirmatory step for qualitative determination of the effects of both various saline and serum concentrations on the biofilm formation, which induces similar results. Environmental stressors modulate S. aureus biofilm formation in a dose-dependent manner via regulation of the ica operon and sarA, offering molecular insights that may guide strategies for biofilm control. KEY POINTS: • Oxidative stress (H₂O₂) dose-dependently inhibits S. aureus Newman biofilms. • Mild NaCl levels enhance biofilm formation via upregulation of ica and sarA. • High serum concentrations (≥ 20%) suppress biofilm biomass and gene expression.

Esophageal squamous cell carcinoma (ESCC) remains a deadly disease, with no effective therapeutics available for advanced stages. The application of the "synthetic lethality" principle to cancers with abnormal epigenetic changes provides more opportunities for developing novel therapeutic strategies. It is necessary to identify more molecules that are involved in the DNA damage repair response or cell fate determination to reach this end. Malignant brain tumor (MBT) domain proteins are important for development and cell fate. L3MBTL4 is a new member of this family, but its function remains to be clarified.

Gastric cancer (GC) is one of the most common and lethal cancers globally. methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) RNA methylation plays a crucial role in tumor initiation and progression by regulating RNA function. STM2457, a highly efficient METTL3 inhibitor, can inhibit METTL3 activity and may serve as a potential therapeutic strategy in cancers. However, the role of STM2457 for GC cells is still unknown. In this study, we analyzed the expression profile data of GC in TCGA and GEO databases, and further explored the expression involvement of METTL3 in GC cell line, investigated the therapeutic effect of STM2457 targeted inhibition of METTL3 in GC both in vitro and in vivo experiments. The results indicated that STM2457 could suppress GC cell proliferation and migration by inhibiting METTL3, and also promoted cell apoptosis and arrest the cell cycle in S phase. In addition, STM2457 could inhibit tumor growth in subcutaneous xenotransplantation mouse model. Our findings suggested that STM2457 had great potential for the treatment of GC and could serve as a foundation for future clinical applications.

Vitamin D (VD) deficiency is commonly observed in obesity, which may increase morbidity risk. This study explores the effect of fructooligosaccharide (FOS) on VD signaling and inflammatory status in diet-induced obese mice.

Epigenetic dysregulation is a fundamental cancer hallmark, and lysine demethylase 1 (LSD1) is a central target for cancer intervention. Developing novel LSD1 inhibitors with high selectivity, favorable bioavailability, and safety for acute myeloid leukemia (AML) remains challenging. We developed DC551040, a highly potent, selective irreversible LSD1 inhibitor with good tolerability in Phase I AML clinical trial (CTR20222026). DC551040-LSD1 complex crystal structure uncovered a new binding pocket, providing molecular insights for subsequent LSD1 inhibitor design. Given the significant role of LSD1 in epigenetic regulation, we performed comprehensive transcriptomic and proteomic analyses to investigate gene and protein expression dynamics following DC551040 treatment in an MV-4-11 xenograft model. These analyses revealed that multiple immune and inflammation related pathways are activated upon DC551040 treatment, including the key members STAT5, NF-κB, and AKT, suggesting the potential for adaptive resistance. Through a search of the Connectivity Map (CMAP) database, we identify homoharringtonine (HHT), an approved anti-leukemia drug, which mimics the anti-transcriptional activation of inflammatory pathways. Subsequent in vitro and in vivo experiments validated the efficacy of combining HHT with DC551040, demonstrating a synergistic antitumor effect and extended survival in MV-4-11 disseminated xenograft model mice. Together, this study not only introduces a novel LSD1 inhibitor but also delves into the molecular mechanisms underlying LSD1 inhibitors, while proposing a promising combination therapy for AML individuals in clinical trials.

Conventionally, KDM5C functions as a specific demethylase that targets histone H3 lysine 4 dimethyl and trimethyl modifications, crucial for gene expression. However, the role of KDM5C in multiple myeloma (MM) progression and bortezomib (BTZ) resistance has remained elusive. In this study, we found noncanonical functions of KDM5C in MM. Specifically, KDM5C binds to CBP and MYC, conferring BTZ resistance in MM through a demethylase-independent mechanism. Our investigations revealed that KDM5C is markedly upregulated in BTZ-resistant MM patients as well as those with relapsed MM. Significantly, the expression level of KDM5C exhibits an inverse correlation with the overall survival of MM patients. Moreover, KDM5C is indispensable for MM cell proliferation. Depletion of KDM5C augmented the sensitivity of MM cells to BTZ treatment both in vitro and in vivo. We found that KDM5C forms a novel complex with CBP and MYC via its PHD2 domain. This complex formation triggers lysine 27 acetylation in histone H3 (H3K27ac) and subsequent enrichment of H3K27ac on the PERK promoter. As a result, PERK transcription is activated, and Nrf2 phosphorylation is promoted, bolstering the unfolded protein response within the endoplasmic reticulum of MM cells. In contrast, the methylation status of histone H3 lysine 4 (H3K4me1/3) on the PERK promoter remains unaltered, regardless of the complex state. Taken together, the findings of this study underscore the key role of KDM5C as a driving force behind MM progression and BTZ resistance, indicating that KDM5C represents a novel and promising therapeutic target for the treatment of BTZ-resistant MM.

This study aims to systematically investigate the molecular mechanisms through which parabens may contribute to head and neck squamous cell carcinoma (HNSCC) carcinogenesis using integrated network toxicology and molecular docking.

Streptococcus mutans (S. mutans) is a primary cariogenic pathogen responsible for acid production, exopolysaccharides (EPS) production and biofilm formation. Two-component systems (TCS) regulate EPS metabolism, especially the VicRK TCS. Overexpression of antisense vicR (ASvicR) can reduce EPS production and thereby weaken the cariogenicity of S. mutans. Although the antimicrobial monomer dimethylaminohexadecyl methacrylate (DMAHDM) exhibits potent antibacterial properties, mature S. mutans biofilms can protect themselves by extracellular matrix. Emerging evidence suggests that genetic intervention enhances drug efficacy, yet the underlying regulatory mechanisms remain largely unexplored.

To explore the protective effects of cassia polysaccharides on myopia by examining their influence on ARPE-19 cells with reduced PAX6 expression.