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.

Bisphenol S (BPS) is ubiquitously used as a substitute for Bisphenol A (BPA) in various consumer and industrial products. However, recent evidence has shown its detrimental effects on human health. Moreover, toxicological data regarding its cyto-genotoxic potential remains underreported. This study evaluated the BPS induced dose dependent cytotoxicity, DNA damage and DNA repair related gene expression in Madin-Darby Bovine Kidney (MBDK) cell line. In MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, a significant reduction in cell viability was observed as the concentrations of BPS increased, with 50% of viability noted at 120 µM following 24 hrs exposure. Cyto-genotoxic effects were assessed using alkaline comet and micronucleus assays. A dose-dependent increase in DNA damage and micronucleus frequency was observed, especially above 120 µM dose concentration of BPS (P ≤ 0.05). The gene expression analysis through quantitative real time PCR (qRT-PCR) revealed upregulated expression rates of 8-Oxoguanine DNA Glycosylase 1 (OGG1) and hypoxanthine phosphoribosyltransferase 1(HPRT 1), particularly at 240 µM of BPS (P ≤ 0.05). This upregulation suggests the activation of oxidative DNA repair and nucleotide salvage pathways as triggered responses to genotoxic stress. The results of this study raise serious concerns regarding the cyto-genotoxic safety of BPS, thereby warranting the urgent need to reassess its safety profile and regulate its widespread use.

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.

Bisphenol A (BPA), an endocrine-disrupting chemical with estrogenic activity, has been implicated in cancer development, although its role remains controversial. This study investigated the effects of BPA on ovarian cancer and its underlying mechanisms. BPA treatment dose-dependently (0-10 μM) increased cell viability and invasion. Kyoto Encyclopedia of Genes and Genomes analysis revealed the enrichment of the central carbon metabolism pathway following BPA exposure. Consistent with this, BPA upregulated glycolytic enzymes HK2 and LDHA. In addition, BPA activated ERα, which enhanced HK2 transcription and promoted glycolysis. The resulting lactate accumulation increased histone H3 lysine 18 lactylation (H3K18la), enriched at the IGF2BP3 promoter, to upregulate its expression. IGF2BP3 then stabilized HK2 mRNA via m6A recognition, amplifying the glycolysis. Our findings suggest that BPA promotes ovarian cancer progression through the HK2/H3K18la/IGF2BP3 sequential regulatory axis, providing insights for epigenetic-targeted therapies.

Mycotoxins are toxic secondary metabolites produced predominantly by fungal genera, such as Aspergillus, Fusarium, and Penicillium, and represent major foodborne contaminants responsible for chronic human exposure worldwide. While aflatoxin B1 (AFB1) is a well-established hepatocarcinogen, increasing evidence indicates that multiple mycotoxins contribute to tumorigenesis across diverse organ systems through shared biochemical and molecular mechanisms. At the molecular level, mycotoxins undergo cytochrome P450-mediated bioactivation, generating reactive intermediates that induce DNA adduct formation, oxidative stress, genomic instability, and disruption of redox homeostasis. These events converge on dysregulation of key signaling pathways governing cell-cycle control, apoptosis, immune surveillance, and epigenetic regulation, including aberrant DNA methylation, histone modification, and non-coding RNA expression. Importantly, emerging data support a "dual-hit" paradigm in which mycotoxin exposure synergizes with oncogenic viral infections, such as hepatitis B virus (HBV), human papillomavirus (HPV), and Epstein-Barr virus (EBV), amplifying genotoxic stress, immune evasion, and epigenetic instability. This review synthesizes current mechanistic insights into mycotoxin-induced carcinogenesis, emphasizing molecular toxicological endpoints that link exposure to cancer risk. In addition, advances in biosensing, detoxification, and preventive strategies are discussed, highlighting the need for mechanism-driven interventions to mitigate mycotoxin-associated carcinogenicity and its public health burden.

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.

Multi-omics analysis reveals that isofl avonoid biosynthesis and gene-specifi c DNA methylation are key mechanisms underlying cadmiumtolerance in soybean. Cadmium (Cd) contamination poses a significant threat to crop productivity and food safety. Yet, the genetic and epigenetic mechanisms of Cd tolerance in soybean remain unclear. This study investigated the physiological, molecular, and epigenetic responses of 25 soybean germplasms grown hydroponically under Cd stress (20 µM). Tolerance coefficients and variability analyses revealed distinct responses among cultivars. Principal component and cluster analyses classified the germplasms into five groups, with ZH35 and ND257 identified as the most tolerant, while MRidge and JXD were the most susceptible cultivars. Tolerant lines maintained better growth and antioxidant defense, whereas susceptible cultivars accumulated higher levels of oxidative damage (hydrogen peroxide-H2O2 and malondialdehyde-MDA). Gene expression profiling and weighted gene co-expression network analysis (WGCNA) revealed stress-responsive modules, with the sensitive cultivar upregulating photosynthesis-related pathways under control conditions, while the tolerant cultivar under Cd stress exhibited upregulation of isoflavonoid biosynthesis, consistent with metabolomic patterns. DNA methylation profiling of selected germplasms uncovered differentially methylated promoter regions in genes linked to photosynthesis and isoflavonoid biosynthesis, validated by qPCR and McrBC-PCR. Together, the findings highlight key molecular and epigenetic features associated with Cd tolerance, offering valuable insights and potential targets for breeding stress-resilient soybean cultivars.

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.

Chemotherapy resistance, particularly resistance to oxaliplatin, remains a major clinical challenge in the treatment of colorectal cancer (CRC). Ferroptosis, a newly characterized form of regulated cell death, has emerged as a potential mechanism for overcoming chemotherapy resistance. The transcription factor FOSL1 has been implicated in CRC progression and chemoresistance; however, its role in ferroptosis is not well defined.

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.

The distinct chemical behaviors of Cadmium (Cd) and arsenic (As) make the co-contaminated paddy soils pose severe risks to rice safety and public health. This study first demonstrates the manganese(II) sulfate (MnSO4) mitigates Cd and As co-accumulation and co-toxicity in rice, and elucidates the underlying mechanisms by employing integrated ionomic, transcriptomic and metabolomic analyses. Application of moderate to high doses of MnSO4 in pot experiments increased brown rice yield by 208.78-428.60% while reducing Cd and As content by 4.89-21.98% and 60.65-81.73%, respectively. MnSO4 mediates Cd distribution through direct competitive antagonism, whereas As sequestration is governed by more complex and indirect regulatory pathways. The MnSO4 amendment also orchestrates a remodeling of the mineral element network by regulating key genes and metal transporters. This mechanism ultimately limits the accumulation of Cd and As in the grain via distinct pathways: by hindering root to brown rice Cd translocation and inhibiting stem/leaf to brown rice As translocation. Transcriptomic and metabolomic analysis further revealed that Mn alleviates combined Cd-As stress by downregulating key pathways involved in lipid peroxidation and sphingolipid metabolism, thereby enhancing cellular membrane stability. Collectively, MnSO4 integrates transporter regulation, ionomic reconfiguration, and metabolic adaptation to alleviate Cd-As co-stress in rice. Our findings provide a effective approach to ensure rice safety in contaminated regions.

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.

Methine sulfoxide reductase (MSR) plays a crucial role in protecting plants from oxidative damages. However, their involvement in copper (Cu) detoxification remains largely uncharacterized. In this study, we identified 17 MSR genes in wheat (Triticum aestivum), 12 MSR genes in Triticum dicoccoides (Td), 6 in Triticum urartu (Tu), and 5 in Aegilops tauschii (Aet). Strong collinearity and conservation were found among orthologs. Three constitutively expressed homoeologs of TaMSRB5 were significantly upregulated in leaves and downregulated in roots of wheat seedlings when exposed to excessive Cu. Overexpression of TaMSRB5 in Arabidopsis significantly enhanced Cu tolerance as evidenced by increased fresh weight and root length in transgenic plants, compared to wild-type (WT, Col-0). Under Cu toxicity, Arabidopsis overexpression lines accumulated similar levels of Cu in their leaves and roots compared with WT. However, they exhibited elevated levels of oxidized glutathione (GSSG), total glutathione (T-GSH), along with Glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activities. Simultaneously, they showed reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and a lower GSH/ GSSG ratio, indicating enhanced ROS scavenging ability. Consistent with the moderation of oxidative stress, comparative transcriptome analysis revealed that four GST genes were upregulated in transgenic Arabidopsis plants under Cu stress, suggesting the potential relationship between these genes with TaMSRB5 in Cu detoxification. The findings demonstrate the pivotal role of TaMSRB5 in enhancing Cu tolerance in Arabidopsis and provide novel insights into the molecular mechanisms underlying Cu detoxification.

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.