Substitute for perfluorooctanoic acid (PFOA), like hexafluoropropylene oxide trimer acid (HFPO-TA), are sparking growing environmental and health worries because of their persistence and capacity for bioaccumulation. Here, we employed an integrated multi-omics approach to systematically investigate HFPO-TA-induced hepatic lipid metabolic dysregulation in zebrafish. Exposed to a series of concentrations (0, 5, 50, 500 μg/L) of HFPO-TA induced hepatic lipid accumulation and significantly elevated serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Integrated transcriptomic and epigenome analyses revealed that HFPO-TA reprogrammed the hepatic epigenome by selectively activating lipid synthesis-associated enhancers while suppressing lipid oxidation pathways, predisposing to metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, HFPO-TA preferentially remodeled chromatin accessibility and distal enhancers, driving lipogenic gene activation through nuclear receptors, such as peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Finally, functions of PPARα and FXR in HFPO‑TA‑induced lipid imbalance were validated by pharmacological modulators. Overall, our study delivers comprehensive evidence connecting PFOA alternatives to epigenetically driven hepatic steatosis, providing mechanistic understanding to support environmental risk evaluations of emerging perfluoroalkyl and polyfluoroalkyl substances (PFAS) compounds.

Normal fertilization triggers Ca2+ oscillations in the oocyte cytoplasm. Different assisted oocyte activation (AOA) protocols differ markedly in the calcium dynamics, yet their respective impacts on embryo gene expression remain incompletely understood. In this study, we employed strontium chloride (SrCl2), which induces Ca2+ oscillations, A-23187, which induces a single Ca2+ rise, and RO-3306, which activates oocytes without a Ca2+ rise by directly inhibiting CDK1 activity, to estimate the effect of different parthenogenetic activation protocols on embryo gene expression using fertilized embryos as a control. We compared the data of omics among different blastocysts. The transcriptional profiles of diverse parthenogenetic blastocysts were distinct from those of normal blastocysts, while transcriptional levels among different parthenogenetic blastocysts were relatively similar. Similarly, proteomics analysis revealed different protein expression profiles of diverse parthenogenetic blastocysts compared to those of normal blastocysts, especially proteins related to fatty acid biosynthesis, fatty acid β-oxidation metabolic, mitochondria, RNA splicing, and RNA binding. Some protein expression differences were also observed among different parthenogenetic blastocysts. However, all parthenogenetic blastocysts exhibited similar differentially expressed pathways. Our results show that gene expression in parthenogenetic embryos is distinct from that of normally fertilized embryos, and Ca2+ rise, especially Ca2+ oscillation, is important for proper gene expression in early embryos.

Cyclic nucleotide-gated channels (CNGCs) are evolutionarily conserved calcium-permeable non-selective cation channels that play critical regulatory roles in plant abiotic stress responses. This study characterizes HcCNGC11 in kenaf (Hibiscus cannabinus L.) through integrated genomic and functional analyses. Subcellular localization analysis using GFP-fusion constructs confirmed plasma membrane-specific targeting of HcCNGC11. Tissue-specific expression profiling revealed that HcCNGC11 transcripts accumulate predominantly in roots (2.8-fold higher than leaves), followed by leaves, stems, flowers, and seeds. Notably, HcCNGC11 demonstrated rapid transcriptional upregulation under 150 mM NaCl stress, reaching maximum induction at 3 h post-treatment. Virus-induced gene silencing of HcCNGC11 significantly inhibited kenaf growth under salt stress. Biochemical analyses of the silenced lines showed 5-66% reduced activities of antioxidant enzymes (SOD, POD, CAT), decreased osmoregulatory substances (soluble protein, proline), reduced chlorophyll content, and elevated ROS (H₂O₂, O₂·⁻) accumulation. Under salt stress, HcCNGC11-silenced plants displayed significant downregulation of antioxidant enzyme genes (HcSOD, HcPOD, HcCAT) as well as stress-responsive genes (HcP5CS, HcLTP, HcNCED). Conversely, Arabidopsis lines overexpressing HcCNGC11 exhibited 20-47% higher antioxidant enzyme activities, increased osmoregulatory substances, enhanced chlorophyll content, and markedly reduced ROS accumulation compared to WT under salt stress. Molecular analysis of these transgenic lines showed upregulated expression of antioxidant genes (AtSOD1, AtPOD1, AtCAT1) and stress-responsive genes (AtSOS1, AtNHX1, AtCOR15). Protein-protein interaction studies, employing both yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays, identified multiple HcCNGC11 binding partners, including HcCaM7, HcCNGC21, HcTHI1, and HcTCP14. Collectively, these results demonstrate that HcCNGC11 positively regulates plant salt tolerance through modulation of antioxidant systems and stress-responsive pathways.

Glioblastoma is a highly aggressive primary brain tumour marked by extensive genomic and epigenomic alterations, cellular heterogeneity, and therapeutic resistance. Despite maximal surgical resection followed by chemoradiotherapy, median survival remains approximately 15 months, reflecting the tumour's invasive behaviour and adaptability. Advances in molecular oncology have revealed two promising therapeutic directions: epigenetic reprogramming and neurogenetic modulation. Glioblastoma exhibits widespread epigenetic dysregulation that disrupts transcriptional control, enhances cellular plasticity, and drives tumour progression. Concurrently, glioma cells aberrantly reactivate developmental programmes, acquiring neural stem cell-like states governed by transcription factors and signalling networks such as SOX2, OLIG2, Notch, and Wnt. These pathways collectively sustain stemness, lineage mimicry, and therapy resistance. This review proposes a focused conceptual framework centred on epigenetic and neurogenetic modulation as two core regulatory layers shaping glioblastoma plasticity and adaptive resistance. We highlight how DNA methylation, histone modifications, and chromatin remodelling contribute to transcriptional dysregulation, and how neurodevelopmental signalling reinforces malignant plasticity. Emerging preclinical and clinical studies combining epigenetic inhibitors with differentiation- or reprogramming-based therapies are discussed. By uniting mechanistic insights from chromatin biology, neurodevelopment, and cancer therapeutics, this integrative conceptual framework offers a structured lens for targeting key vulnerabilities underlying glioblastoma plasticity. The integration of these complementary strategies offers potential to enhance therapeutic responsiveness and improve disease management in this devastating malignancy.

This study aims to bridge toxicological target prediction and bladder cancer transcriptomics by systematically identifying molecular signatures and pathways that converge between PFOA-associated toxicological effects and bladder cancer biology, using an integrative multi-cohort computational framework.

Growing evidence indicates that nanoplastics (NPs), particularly polystyrene nanoparticles (PS-NPs), cross the blood-brain barrier and reach the hippocampus, where they induce neurotoxicity through oxidative stress, neuroinflammation, and synaptic damage. In the present study, we demonstrate that PS-NPs downregulate RNF139 in microglia, impairing the degradation of SCAP. Elevated SCAP levels trigger SREBP activation, disordered lipid metabolism, and enhanced lipid synthesis. Subsequently, mitochondrial dynamics are dysregulated, characterized by elevated mitochondrial reactive oxygen species, a drop in membrane potential, and diminished ATP synthesis. Under these pathological conditions, microglia become abnormally activated and secrete inflammatory factors such as TNF-α, IL-1β, and IL-6. This neuroinflammatory cascade induces neuronal damage and apoptosis, resulting in spatial cognitive impairment. Thus, our findings reveal a link between PS-NPs exposure, changes in microglial lipid metabolism, and nerve damage. They also identify targets for treating NP-induced neurological disorders.

SR12813 is an experimental cholesterol-lowering drug that reduces intracellular cholesterol through accelerated proteasomal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and is also recognized as a prototypical activator of the pregnane X receptor (PXR, NR1I2). Rifampicin, a clinically used antibiotic, likewise functions as a human PXR agonist. Although PXR-mediated induction of drug metabolism genes has been extensively characterized in hepatocytes and humanized mouse liver, comparatively little is known about the transcriptional effects of these ligands in intestinal and colon cancer cells. Here, we used RNA-sequencing in LS180 colon adenocarcinoma cells to compare transcriptional responses elicited by SR12813 and rifampicin. Both compounds induced canonical PXR targets, including CYP3A4, UGT1A1, and MDR1 (P-glycoprotein), whereas SR12813 preferentially upregulated genes associated with ketone body metabolism, lipid storage, and glycolysis. Complementary nuclear receptor reporter assays demonstrated that, in addition to robust PXR activation, SR12813 also functions as a partial agonist of peroxisome proliferator-activated receptor gamma, a receptor with critical roles in lipid metabolism and colon cancer biology. These findings demonstrate that SR12813 elicits overlapping, yet distinct transcriptional profiles relative to rifampicin, extending beyond xenobiotic metabolism to include metabolic pathways relevant to tumor progression. Collectively, our results highlight SR12813 as a dual-acting modulator of PXR and peroxisome proliferator-activated receptor gamma, and underscore its utility as a pharmacological tool for investigating nuclear receptor crosstalk in intestinal models. SIGNIFICANCE STATEMENT: SR12813 activates both pregnane X receptor and peroxisome proliferator-activated receptor gamma, demonstrating dual nuclear receptor modulation in colon cancer cells. By linking xenobiotic metabolism with lipid and mitochondrial pathways, this work uncovers previously unreported receptor crosstalk and provides a mechanistic framework for how diverse ligands can differentially shape transcriptional programs relevant to drug metabolism and tumor biology.

Metabolic control of chromatin and gene expression is emerging as a key mechanism influencing critical neuronal functions. Here, we found that the intermediary metabolite acetate enhanced long-term memory in female mice, which was associated with epigenetic and transcriptional remodeling in the dorsal hippocampus. Acetate-enhanced memory was driven by increased acetylation of the histone variant H2A.Z and increased expression of genes implicated in learning in the female dorsal hippocampus. The effect of acetate on dorsal hippocampal histone modifications and gene expression differed markedly between the sexes during critical windows of memory consolidation and recall, and home cage exposure to acetate without the learning and recall tasks did not recapitulate these effects. These findings elucidate the ways in which acetate exposure enhances memory.

In the present study, we found that OsHIPP53 can directly bind Cd ions and possesses the capability to modulate Cd tolerance and accumulation in rice. Cadmium (Cd) pollution represents a widespread environmental issue in agricultural regions in China, adversely affecting crop productivity and threatening food safety. Heavy metal-associated isoprenylated plant proteins (HIPPs), a major class of metallochaperone proteins, are essential for plant adaptation to diverse biotic and abiotic stress conditions. This study characterizes a previously uninvestigated HIPP gene, OsHIPP53, demonstrating its involvement in modulating Cd accumulation and tolerance in rice. Subcellular localization analysis revealed that OsHIPP53 is primarily localized at the plasma membrane and Cd exposure significantly induced its transcriptional level in root tissues. Heterologous expression of OsHIPP53 in Δycf1 yeast mutants conferred improved Cd resistance and reduced cellular Cd levels relative to yeast cells carrying the empty vector. The results of the in vitro metal-binding assays indicate that OsHIPP53 can directly bind Cd ions. Consistent with yeast findings, in rice, oshipp53 mutant lines (oshipp53-1 and oshipp53-2) exhibited heightened Cd sensitivity, elevated root Cd concentrations, and restricted Cd translocation to the shoots. Conversely, overexpression lines (OsHIPP53-OX-1 and OsHIPP53-OX-2) displayed greater Cd tolerance and Cd accumulation in the shoots. Taken together, these results suggested that OsHIPP53 functions in regulating Cd tolerance and accumulation in rice.

Metastatic melanoma, marked by its poor prognosis and frequent recurrence, is a particularly aggressive skin cancer. Jaceidin, a compound derived from flavonoids abundant in common fruits and vegetables, has attracted interest for its potential anti-cancer properties. Nevertheless, the specific effects of jaceidin on melanoma cells remained unclear before this study. Here, we examined the impact of jaceidin on two metastatic melanoma cell lines, HMY-1 and A2058. Our results demonstrate that jaceidin exerts a significant anti-metastatic effect against both cell lines. This inhibitory action involved modulating the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase, as well as suppressing proteins associated with epithelial-mesenchymal transition. Furthermore, jaceidin reduced the expression of extracellular matrix degradation proteins MMP-2 and cathepsins A. These compelling findings suggest that jaceidin warrants further investigation as a potential therapeutic agent for melanoma.

Insect wing development involves tissue patterning, cell fate transitions, and hormone signaling, yet its spatiotemporal logic remains unclear. The silkworm, with large wing discs and defined stages, provides an ideal model for high resolution analysis. Here, we construct a spatiotemporal single-cell atlas of the silkworm wing disc across 10 timepoints, identifying 12 major cell types and their developmental transitions. Wing morphogenesis (Wm) cells act as central progenitors, differentiating into epithelial and cuticle lineages under lineage-specific transcription factors. Time‑resolved snRNA‑seq reveals hierarchical transcriptional reprogramming, with Wm cells functioning as early signaling hubs. Functional modules and signaling pathways were activated in spatiotemporal controlled manner. 20‑hydroxyecdysone treatment rapidly accelerates fate transitions and gene expression, recapitulating natural development within hours. Integration of morphology, hormone levels, and gene expression supports a five-stage Gene Transition Model describing progressive fate resolution. This work reveals wing development in silkworm and provides insights into hormone-driven organogenesis and potential manipulation of insect development in agriculture.

The present study aimed to reveal the effects of Astragalus membranaceus polysaccharide (APS) on antioxidant capacity, immune-related gene expression, and inhibition of grass carp reovirus (GCRV) proliferation in grass carp (Ctenopharyngodon idella). Grass carps were fed experimental diets containing either 0.0% or 0.2% APS for 40 days. The results showed that APS supplementation significantly enhanced antioxidant capacity, as evidenced by increased activities of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). Moreover, APS upregulated immune-related parameters, including immunoglobulin M (IgM), complement 3 (C3), complement factor B (Bf), mannose-binding lectin (MBL), lysozyme (LSZ), and C-X-C motif chemokine 13 (CXCL13), and modulated the expression of inflammatory cytokines such as interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), and interleukin 10 (IL-10). Furthermore, APS feeding markedly induced the expression of antiviral genes, including interferons (IFNs), interferon regulate factors (IRFs), and interferon stimulate genes, (ISGs)in the spleen, kidney, liver, and head kidney. Following intraperitoneal challenge with GCRV, the survival rate of the APS-treated group (76.67%) was significantly higher than that of the control group (43.33%). In addition, APS supplementation substantially reduced the relative protein levels of virus protein 5 (VP5)and virus protein 7 (VP7)during GCRV infection. These findings suggest that dietary APS enhances resistance to GCRV in grass carp by promoting immune fuction and antiviral responses. Collectively, our results demonstrate that APS effectively boosts immune activity and improves capacity of grass carp to combat GCRV infection. This study provides a theoretical basis and practical reference for the application of APS in the prevention and control of fish diseases.

Cyclic GMP-AMP synthase (cGAS) catalyzes the production of cGAMP, which activates the STING-IRF3 signaling pathway. Previous investigations indicated a role for STING-IRF3 in early alcohol-associated liver disease (ALD). In this study, we examined the role of cGAS in liver damage and inflammation in early ALD.

Glyphosate is the most widely used herbicide globally, especially due to the extensive cultivation of genetically modified glyphosate-resistant crops. However, its intensive application has raised public concerns about the risks to food safety and human health. Identifying enzymes capable of metabolizing glyphosate in plants represents an ideal strategy for addressing this issue, but few are known. Here, we identified the rice variety Kitaake with natural tolerance to glyphosate and demonstrated that this tolerance is driven by glyphosate glycosylation metabolism. Seven up-regulated UDP-dependent glycosyltransferase (UGT) genes associated with glyphosate tolerance were identified in Kitaake. Molecular-docking analysis indicated that these UGT proteins have moderate binding affinity for glyphosate. Among these, a deletion of an adenine at position -803 in the promoter region of GLYPHOSATE RESPONSIVE GLYCOSYLTRANSFERASE 1 (GRGT1) enhances its expression in Kitaake. GRGT1 localizes to the endoplasmic reticulum and catalyzes glyphosate glycosylation both in vivo and in vitro. Rice lines complemented with GRGT1-GFP rescue the inability of grgt1 knockout mutants to produce glycosylated glyphosate derivatives. Overexpression of GRGT1 in the susceptible Nipponbare cultivar confers glyphosate tolerance by up-regulating glyphosate metabolism to produce glycosylated glyphosate derivatives M329, M331, and M345. This provides a strategy for developing herbicide-tolerant crops, but also offers a potential approach to consequently reduce glyphosate residues in crops.

CRISPR interference (CRISPRi) screens have emerged as powerful tools for dissecting gene function, yet their application to genes with multiple promoters, which comprise over 60% of human genes, remains poorly understood. Here, we demonstrate that CRISPR-dCas9-based screens exhibit widespread promoter specificity, with untargeted promoters often showing compensatory upregulation to maintain gene expression. Leveraging this selective targeting of individual promoters within the same gene, we developed Isoform-Specific single-cell Perturb-Seq to systematically analyse alternative promoter function. Our analysis revealed that alternative promoters in 51.6% of targeted genes drive distinct transcriptional programs. This suggests that promoter selection represents a fundamental mechanism for generating cellular diversity rather than mere transcriptional redundancy. In breast cancer models, this promoter-specific targeting revealed differential effects on drug sensitivity, where distinct estrogen receptor (ESR1) promoters showed opposing influences on tamoxifen response and patient survival. These findings demonstrate the necessity of promoter-level analysis in functional genomics and suggest new strategies for therapeutic intervention through promoter-specific targeting.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen for which new antimicrobial strategies are urgently needed. To facilitate the establishment of the infection, P. aeruginosa produces a remarkable assortment of both cell-associated and extracellular virulence factors. The expression of numerous virulence traits is regulated by the pqs quorum sensing (QS) system, which relies on multiple enzymes for the biosynthesis of 2-alkyl-4-quinolone (AQ) signal molecules and on the transcriptional regulator PqsR, whose activity is triggered by AQ binding. Herein, we report on the design and synthesis of novel quinazolinone-based PqsR modulators, which led to the identification of two novel compounds endowed with anti-PqsR activity in the submicromolar range. Additionally, these derivatives inhibited the production of PqsR-controlled virulence factors in laboratory strains and clinical isolates of P. aeruginosa.

Non-small cell lung cancer (NSCLC) treatment faces significant challenges due to drug resistance and toxicity. Emerging evidence suggests that ferroptosis, an iron-dependent form of regulated cell death, is a promising therapeutic strategy. We identify Pinostilbene, a natural stilbenoid, as a potent and novel STING agonist. Our findings reveal that Pinostilbene effectively activates the STING/TBK1/IRF3 pathway, leading to the transcriptional upregulation of downstream cytokines. Importantly, we demonstrate that Pinostilbene significantly enhances the sensitivity of lung cancer cells to RSL3-induced ferroptosis. Mechanistically, Pinostilbene promotes the degradation of the iron-storage protein Ferritin Heavy Chain 1 (FTH1), a key negative regulator of ferroptosis. We uncover a novel mechanism in which Pinostilbene induces FTH1 degradation through the ubiquitin-proteasome system via K48-linked polyubiquitination, a process independent of NCOA4-mediated ferritinophagy. This FTH1 degradation increases the labile iron pool, a critical prerequisite for ferroptosis. In vivo, Pinostilbene exhibits robust antitumor efficacy alone and achieves synergistic tumor growth inhibition when combined with RSL3 in a NSCLC mouse model without systemic toxicity. Its therapeutic effect is linked to STING activation and FTH1 downregulation, which coincides with an increase in the ferroptosis biomarker 4-HNE. Furthermore, Pinostilbene enhances antitumor immunity by upregulating inflammatory cytokines and promoting the infiltration and activation of tumor-killing CD8+ T cells, alongside drving anti-tumor M1 polarization of macrophages. Our study highlights the potential of Pinostilbene as a promising therapeutic agent for NSCLC, offering a multifaceted mechanism of action through ferroptosis sensitization and immunostimulation.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, primarily due to its highly fibrotic and immunosuppressive tumor microenvironment (TME), which limits both drug delivery and immune cell infiltration. Epigenetic dysregulation plays a pivotal role in shaping these barriers by controlling transcriptional programs that govern tumor-immune interactions, stromal remodeling, and immune evasion.This review synthesizes current insights into the contribution of aberrant epigenetic mechanisms to PDAC progression and immune resistance. We outline how epigenetic alterations suppress antigen presentation, sustain immunosuppressive cell populations, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and upregulate immune checkpoint molecules across cancer and stromal compartments. Emerging evidence shows that epigenetic therapies targeting DNA methyltransferases, histone deacetylases, histone methyltransferases, or bromodomain proteins can restore tumor immunogenicity, reprogram cancer-associated fibroblasts, and promote cytotoxic T cell infiltration. Furthermore, combining epigenetic modulators with immune checkpoint blockade or targeted therapies has demonstrated the capacity to remodel the PDAC TME and convert immunologically 'cold' tumors into more responsive ones. Therefore, we also summarize key completed and ongoing clinical trials in PDAC and solid tumors, emphasizing outcomes and biomarker discoveries that support the translation of epigenetic-immunotherapy combinations into clinical practice. Finally, we discuss persistent challenges that impede progress, including poor drug penetration through the desmoplastic stroma, off-target effects and toxicity of epigenetic agents, tumor hypoxia, adaptive resistance, and the scarcity of physiologically relevant immuno-oncology models.Findings from preclinical and early clinical studies indicate that epigenetic reprogramming represents a promising avenue to overcome PDAC immunoresistance by reactivating antigen presentation, disrupting immunosuppressive cellular networks, and enhancing antitumor immunity. However, realizing this potential will require rationally designed combination regimens, predictive biomarkers for patient stratification, and a deeper understanding of cell type-specific and context-dependent epigenetic regulation. Only through these advances can the integration of epigenetic modulation with immunotherapy and stroma-targeting approaches ultimately redefine therapeutic strategies for patients with PDAC.

Osimertinib resistance remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in tumor microenvironment (TME), however, its role in osimertinib resistance in NSCLC is not fully understood. In this study, it was found that CAFs promoted osimertinib resistance in NSCLC cells via elevating RNA m7G modification. Methyltransferase 1 (METTL1) in NSCLC cells mediated CAFs' effect on m7G modification, and METTL1 was associated with NSCLC progression and poor prognosis. Further study demonstrates that CAFs upregulated METTL1 in NSCLC cells by secreting HMGB1. By applying MeRIP-seq and RNA-seq, neuroepithelial cell transforming gene 1 (NET1) was identified as a target of METTL1, and enhanced m7G modification of NET1 increased NET1 expression and activated downstream AKT/NF-κB pathway. Importantly, reducing m7G modification by METTL1 knockdown significantly attenuated CAFs' stimulatory effect on osimertinib resistance both in vitro and in vivo. Our study revealed a novel mechanism that CAFs conferred osimertinib resistance in NSCLC cells through modulating m7G modification. These findings underscore the importance of m7G modification in the communication between cancer cells and the TME, and pave the way for finding novel therapeutic strategies to overcome drug resistance by targeting m7G modification.

Despite the transformative impact of osimertinib as a cornerstone targeted therapy for advanced EGFR-mutant non-small cell lung cancer, the emergence of acquired resistance ultimately limits its long-term efficacy. While genetic alterations, tumor microenvironment dynamics, and cancer stem cells contribute to resistance, they inadequately explain its rapid adaptive evolution. This critical knowledge gap points to an underexplored dimension of resistance: the dynamic reprogramming of the epigenetic landscape. This review establishes dynamic histone plasticity--driven by imbalances in key epigenetic modifications such as acetylation and methylation, along with newly recognized marks including lactylation--as a pivotal epigenetic driver of resistance. Evidence demonstrates that these modifications remodel chromatin architecture, reprogram transcriptional networks, compromise DNA damage repair, and stabilize a drug-tolerant persister state, collectively accelerating tumor adaptation during therapeutic pressure. Beyond mechanism, distinct histone-modification signatures are emerging as promising predictive biomarkers for resistance, simultaneously revealing novel, pharmacologically targetable epigenetic vulnerabilities. Leveraging next-generation technologies, we propose an integrated strategy: multimodal epigenetic therapies combined with real-time liquid biopsy profiling to shift from reactive management toward predictive prevention of resistance. By bridging deep epigenomic mechanistic understanding with innovative diagnostic and therapeutic tools, this roadmap provides a proactive, adaptive framework designed to circumvent tumor evolutionary pathways, overcome therapeutic resistance, and prolong patient survival.