λ-Carrageenan (λ-CGN) has attracted attention for its biological activities, such as anticoagulant, antitumor, and pro-inflammatory effects. Here, we explored the function of λ-CGN in modulating innate immune responses. Our study showed that λ-CGN inhibited the infection by various viruses. Mechanistically, λ-CGN mediated inflammatory responses by activating classical NF-κB signaling. Importantly, λ-CGN attenuated K48 ubiquitination of IRF3, thereby promoting IRF3 protein stability and activating IRF3-mediated type I IFN responses. Furthermore, orally administered λ-CGN attenuated the pathogenicity of PRV and VSV in mice. These results demonstrate a novel mechanism by which λ-CGN modulates immune responses and support λ-CGN as a potential antiviral drug.

Immune checkpoint blockade (ICB) has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy remains limited. Recent studies demonstrate that resistance to ferroptosis is a significant barrier to the success of ICB.

Doxorubicin (DOX) is an effective anticancer therapeutic but exhibits dose-dependent, potentially life-threatening cardiotoxicity. The specific mechanisms driving this cardiotoxicity are not fully understood but can include the induction of oxidative stress and subsequent cell death mechanism activation. This has prompted the exploration of NRF2, a master co-ordinator of antioxidant and largely cytoprotective pathways, as a potential approach for the alleviation of DOX-induced cardiotoxicity. Here, NRF2 was pharmacologically activated via CDDO-Me (hitherto referred to as CDDO) to reduce the negative consequences on AC16 human cardiomyocyte cell health and functions. NRF2 intracellular dynamics were quantitatively measured using live-cell imaging, demonstrating rapid (∼10 min) yet sustained (≥24 h) induction of NRF2 expression and functional downstream activity. Genetic perturbations of the NRF2-KEAP1 system highlight that CDDO acts specifically through NRF2 to exert AC16 cytoprotection from DOX whilst not promoting human lung and pancreatic cancer cell line viability. RNA-seq analysis was also utilised to highlight the molecular mechanisms underpinning the effects DOX in AC16 cells and the CDDO-mediated mitigation of cardiotoxicity. This study provides novel insight into NRF2 dynamics in the widely utilised AC16 cells whilst further elucidating the molecular mechanisms contributing to DOX cardiotoxicity and potential NRF2-orchestrated defence.

Erianin, a natural bibenzyl compound, has recently garnered attention owing to its diverse biological activities. In the present study, we investigated the effects of Erianin on adipocyte differentiation, lipid metabolism, and mitochondrial respiration in murine 3T3-L1 cells. Cytotoxicity assays indicated that Erianin exhibited low toxicity towards preadipocytes at concentrations up to 200 μM. Treatment with 20 μM Erianin completely inhibited the differentiation of 3T3-L1 preadipocytes into mature adipocytes and reduced lipid droplets. Western blot analysis revealed that Erianin attenuated Akt and p38 MAPK signalling without inducing apoptosis, suppressed the expression of key pro-adipogenic transcription factors, C/EBPα and PPARγ during the early stages of differentiation. This suppression was accompanied by the downregulation of lipogenic enzymes, including acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), pyruvate carboxylase (PC) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). While early-stage differentiation was robustly inhibited, higher concentrations (≥25 μM) were required to suppress terminal differentiation of immature adipocytes. This late-stage inhibition was accompanied by decreased expression of PPARγ, PC, and HMGCR, with minimal effects on ACC1 and FASN, suggesting a more modest role for Erianin in terminal adipogenesis. Assessment of mitochondrial metabolism of 3T3-L1 cells following 24-hour treatment of Erianin showed that it modestly impaired ATP-linked respiration, maximal respiration, spare respiratory capacity and intracellular ATP levels while basal respiration was unaffected. Collectively, these findings indicated that Erianin predominantly targets early adipogenic differentiation and mitochondrial bioenergetics.

The pharmacological control of lipid accumulation in white adipose tissue (WAT) is a key area of focus in obesity research, yet the role of deubiquitination in adipocyte lipid storage remains underexplored. We found that spautin-1, an inhibitor of the deubiquitinases ubiquitin-specific peptidase 10 (USP10) and 13 (USP13), suppressed lipid accumulation during adipogenesis. Therefore, we investigated whether blocking deubiquitination restricts adipogenesis and acts as the underlying mechanism. Mining public datasets revealed that USP10 expression is substantially increased in the adipose tissue (AT) from individuals with obesity. Moreover, USP10 exhibited a depot-specific expression pattern, with higher levels in visceral AT than in subcutaneous AT, whereas no such difference was observed for USP13. Consistently, in high-fat diet-fed mice, USP10 was markedly upregulated in gonadal WAT, whereas USP13 was undetectable. Genetic ablation of USP10 phenocopied spautin-1 treatment by reducing the expression of the components of the peroxisome proliferator-activated receptor gamma (PPARγ)/CCAAT/enhancer-binding protein alpha (C/EBPα) axis, while USP13 knockdown induced minimal effects, thus implicating USP10 as the principal mediator. Mechanistically, USP10 directly interacted with C/EBPβ and stabilized it via deubiquitination. However, spautin-1 or USP10 knockdown enhanced C/EBPβ ubiquitination and proteolysis, thereby impairing the adipogenic commitment. The overexpression of wild-type USP10, but not its catalytically inactive mutant, rescued C/EBPβ stability, thus confirming the requirement for its enzymatic activity. The administration of spautin-1 to high-fat diet-fed mice mitigated body weight gain and reduced adipose tissue mass in vivo. Notably, spautin-1 selectively suppressed USP10 and C/EBPβ in gonadal WAT without affecting the liver, which highlights the tissue-specific pharmacodynamics. Collectively, these findings define the USP10-C/EBPβ axis as a key regulator of adipogenesis and position spautin-1 as a mechanistically grounded anti-obesity candidate that warrants translational evaluation.

Exosomes play a crucial role in the transmission of drug resistance in tumors. However, the mechanism of exosomes-mediated transmission in non-small cell lung cancer (NSCLC) under gefitinib treatment remains limited. In this work, we demonstrated that exosomes derived from HCC827/GR cells (drug-resistant) enhanced the survivability of HCC827 cells (drug-sensitive) under treatment with gefitinib. A total of 157 shared upregulated proteins between exosomes and their parent cells were identified in the comparison of the gefitinib-resistant groups versus the gefitinib-sensitive groups. Notably, 69 of these shared proteins are enzymes, and many of them were enriched in pathways related to fatty acid metabolism. Among these enzymes involved in fatty acid metabolism, ACC1 exhibited the highest fold change in upregulated expression in both drug-resistant groups (exosomes and cells). Moreover, the expression of ACC1 was upregulated in gefitinib-sensitive cells after uptake of exosomes from gefitinib-resistant cells. The role of ACC1 in enhancing the survival of HCC827/GR cells under gefitinib treatment was demonstrated using an inhibitor and siRNA-mediated knockdown. Specifically, the upregulated ACC1 stabilized fatty acid oxidation and reactive oxygen species levels in HCC827/GR cells, thereby maintaining cellular metabolic homeostasis. Collectively, this work reveals the transmission of drug resistance in NSCLC via exosomes that carry the ACC1 protein.

Breast cancer (BC) is the most frequently diagnosed cancer among women and the leading cause of cancer-related mortality globally. One of the current systemic therapies against estrogen receptor-positive BC is hormonal therapy with tamoxifen (TAM), a selective estrogen receptor modulator. Recent studies showed that TAM resistance may occur often due to enhanced drug efflux mediated by ATP-binding cassette (ABC) transporters and ultimately can affect treatment efficacy. Epibrassinolide (EBR) is an apoptotic agent by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Continuous activation of UPR was suggested as a strategy to combat drug resistance, underscoring its potential as a therapeutic target.

Cell division cycle 20 homologue (Cdc20), a key regulator of the anaphase-promoting complex/cyclosome (APC/C), is frequently overexpressed in human cancers and represents a promising therapeutic target. However, monotherapy targeting Cdc20 has shown limited efficacy, partly due to compensatory activation of cyclin-dependent kinase 1 (Cdk1). In this study, we investigated the combinatorial potential of the pan-Cdk inhibitor ZK304709 with the Cdc20 inhibitor apcin in HeLa cervical cancer cells. Transcriptomic analysis revealed that both CDC20 and CDK1 are upregulated in cervical cancer tissues. Mechanistically, apcin treatment induced cyclin B1 accumulation and enhanced Cdk1 phosphorylation at Thr161, suggesting feedback activation. In contrast, ZK304709 reduced p-Cdk1(T161) levels and suppressed Cdc20 expression at both protein and mRNA levels. Functionally, the combination of apcin and ZK304709 synergistically inhibited cell proliferation and induced G2/M phase arrest in HeLa cells. These findings demonstrate that dual inhibition of Cdk1 and Cdc20 disrupts compensatory signalling pathways and enhances antitumour efficacy in HeLa cells, providing a rational strategy for combination therapy in cervical cancer.

The novel |Srgap2-Fam72a| master gene, comprising SLIT-ROBO Rho GTPase-activating protein 2 (Srgap2) and family with sequence similarity 72 member A (Fam72a), has attracted attention for its potential role in regulating brain plasticity and supporting advanced cognitive functions in humans. Moreover, recent studies have identified Fam72a as a new cell cycle-regulated gene. In this study, we investigated the activity of the intergenic region (IGR) between the native Srgap2 and Fam72a gene pair and the signaling pathways of Fam72a upon mitogen epidermal growth factor (Egf) stimulation. We found that, under mitogen Egf stimulation, the IGR functions as a divergent promoter, simultaneously driving the transcription of Srgap2 and Fam72a in opposite directions. Furthermore, Fam72a downregulates MIS18 kinetochore protein A (Mis18a), a tightly cell cycle-regulated gene, and interferes with the RAC-alpha serine/threonine-protein kinase (Akt1) signaling pathway by downregulating phosphorylated Akt1 at Serine 473, thereby favoring the more direct mitogen activated protein kinase 1 (Mapk1) route to promote cellular proliferation. These findings provide insight into the role of Fam72a during the cell cycle and suggest that it may contribute to the proliferation of neural stem cells (NSCs).

Salt stress is a major abiotic factor limiting crop productivity. This study investigated the physiological and biochemical responses of peppermint (Mentha × piperita L.) to increasing NaCl concentrations (25, 50, and 100 mM). Terpenoids and flavonoids were analysed by GC-MS and HPLC-ESI-MS/MS, respectively, alongside Real-Time PCR for key biosynthetic genes (menthol biogenesis/Chalcone isomerase) and chlorophyll fluorescence measurements (OJIP, quantum yield, NPQ and PAM). Total terpenoid production decreased significantly (41% at 25 mM, 75% at 100 mM NaCl). Key compounds like menthone (365-71 g/kg), menthol (35-19 g/kg), and 1,8-cineole (58-19 g/kg) were reduced, although pulegone and menthofuran initially increased at moderate salt levels (25 mM) before declining at 100 mM. Mechanistically, this suppression was due to a strategic metabolic bottleneck: upstream terpenoid biosynthetic genes (DXS, GDPS, LS, and L3OH) were upregulated, while terminal-step genes (like menthone/menthol reductase) were progressively downregulated. This metabolic shift correlated strongly with severe photosynthetic impairment, evidenced by reduced quantum yield (0.82-0.61) and altered chlorophyll quenching (0.45-0.28). This impairment likely reduced the precursor supply for terpenoid synthesis. The plant also exhibited selective flavonoid adjustment. While total phenolic content (12.5-7.8 mg GAE g-1 FW) and regulatory gene expression were reduced, the biosynthesis of specific flavonoid conjugates increased (+1.5-fold at high NaCl). These findings reveal that salt stress in peppermint triggers sophisticated and selective metabolic reallocation, severely impacting commercially valuable terpenoids and overall photosynthetic efficiency.

Stomatal guard cells, located at the interface between the leaf and the atmosphere, play a key role in transpiration control and photosynthetic CO2 uptake. Halophytes like Chenopodium quinoa tolerate high soil salinity, but the mechanisms governing guard cell responses to salinity stress in relation to the associated epidermal bladder cells (EBCs) remain unknown. In this study, responses of C. quinoa guard cells under salinity stress and external ABA application were analyzed using RNA profiling and voltage-clamp-based electrophysiology. Under salt stress, guard cell RNA profiles reported the activation of ABA synthesis and signaling pathways. However, unlike EBCs, guard cells exhibited a profoundly attenuated transcriptional response to ABA. Voltage-clamp recordings revealed that under high Na+ concentrations, guard cells' K+-uptake channel activity remained unaffected, while they were impaired in ABA-induced activation of anion channels. As a consequence of a unique guard cell ABA response in salt-adapted plants, stomatal transpiration was reduced and CO2 sensitivity was enhanced. We propose that under salt stress, C. quinoa guard cells rewire their hormone signaling to switch from an ABA-sensitive to a less ABA-responsive mode. This adaptation may reflect the halophyte's ability to perceive salinity as a nonstressful condition, allowing efficient water usage and sustained growth in saline environments.

Fenclorim (Fen), an herbicide safener, mitigates pretilachlor (Pre)-induced phytotoxicity in rice, although its molecular mechanism remains unclear. Previous studies have shown that Fen significantly induces OsGSTF5 expression. This study revealed via molecular docking and in vitro assays that the OsGSTF5 protein binds to and metabolizes Pre. Unlike the wild-type plants, the OsGSTF5-overexpressing lines presented Pre tolerance. Cloning the OsGSTF5 promoter (2.0 kb) identified a Fen-responsive cis-element (-1100 to -1500 bp). Yeast one-hybrid screening revealed that four transcription factors (EIL, AP2/ERF, DBB, and C2H2 families) bind the promoter, as validated by dual-luciferase and qRT-PCR assays. The research results establish a Fen (safener)-mediated detoxification network with OsGSTF5 as the core, promoting our understanding of herbicide action mechanisms. Additionally, for the first time, this study clarifies the inductive regulatory mechanism of safeners in rice.

Vitamin D3 is an essential micronutrient that supports innate immunity and modulates adaptive responses, with in vitro studies implicating epigenetic mechanisms. Yet, in vivo evidence for such regulation remains scarce. Here, we assessed genome-wide epigenomic and transcriptomic responses to vitamin D3 in a high responder from the VitDHiD repeated-measures, non-randomized interventional N-of-1 study, in which the participant received monthly oral boluses of 80,000 IU vitamin D3 over three months. Peripheral blood mononuclear cells (PBMCs) were collected at baseline (day 0) and at 24 and 48 h post-supplementation (days 1 and 2) for ATAC-seq and RNA-seq profiling. ATAC-seq identified > 3,500 regions with increased chromatin accessibility, predominantly at promoters, indicating a strong epigenomic activation. Motif enrichment revealed immune-regulatory transcription factors, but not vitamin D receptor (VDR) motifs, suggesting indirect or cooperative modes of regulation. RNA-seq detected 380 vitamin D-responsive genes with time-dependent expression changes, including DUSP6 and FOS, enriched in pathways related to innate immunity and interferon signaling. Integrative analysis linked 306 differentially expressed genes to vitamin D-sensitive chromatin regions. Many of these overlap with VDR binding sites or promoters of neighboring non-target genes, suggesting potential long-range regulation. Shared enhancers and promoters among neighboring genes indicated redundancy in regulatory architecture. Analysis of PBMCs from 13 participants in the VitDPAS non-randomized interventional cohort study, each receiving a single vitamin D3 bolus, confirmed the main findings from the N-of-1 study but also revealed pronounced inter-individual variability in epigenomic and transcriptomic responses. Together, these results provide in vivo evidence that vitamin D signaling directly and indirectly modulates chromatin accessibility and gene expression, emphasizing its role as an epigenetic regulator of immune function and supporting its potential in personalized nutrition and immune health strategies.

Cervical cancer poses a significant threat to women's health. Although folic acid (FA) has been recognized as a protective factor in cervical carcinogenesis, its precise molecular mechanisms remain incompletely understood. Here, we identify Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), an inhibitor of the Wnt signaling pathway, as a potential target of FA. This study provides systematic evidence that DKK3 expression decreases during cervical squamous epithelial carcinogenesis, showing progressive downregulation from squamous intraepithelial lesions to squamous cell carcinoma, which correlates with advanced FIGO stage and lymphovascular space invasion. Functional assays confirmed DKK3's tumor-suppressive role and therapeutic potential. DKK3 overexpression downregulated β-catenin protein levels and inhibited malignant behavior in SiHa cells, whereas its knockdown produced opposite effects. Notably, this study demonstrated for the first time that FA intervention upregulated DKK3 expression, suppressed Wnt/β-catenin signaling, leading to a reduction in β-catenin protein abundance, and exerted potent anti-tumor effects-suppressing proliferation, migration, and invasion while promoting apoptosis. Even under DKK3-knockdown conditions, FA intervention partially reversed β-catenin accumulation by enhancing residual DKK3 expression. Overall, this study establishes the prognostic and interventional value of DKK3 in cervical squamous epithelial carcinogenesis. FA intervention may serve as an effective strategy to restore DKK3 expression to inhibit the Wnt/β-catenin pathway, thereby exerting antitumor activity. Future cervical cancer prevention and treatment strategies may benefit from dynamic monitoring of DKK3 expression to identify potential beneficiaries and provide targeted FA intervention.

Prostate cancer is estimated to contribute to over 35,000 deaths of men residing in the United States, with the majority fatality due to metastatic disease. CDC7 is a kinase that regulates DNA replication and is found elevated during neuroendocrine transdifferentiation in lung and prostate cancer. In this study, we demonstrate that CDC7 is highly expressed in treatment-resistant prostate cancer, with even higher levels observed in treatment-resistant prostate cancer with neuroendocrine phenotype (NEPC). We further identify CDC7 as a critical regulator of prostate tumorigenesis. Downregulation of CDC7 significantly reduces prostate cancer cells growth and invasion in vitro and silencing CDC7 suppresses prostate tumor growth in vivo. Furthermore, we demonstrate that the inhibition of CDC7 using TAK-931, a selective CDC7 inhibitor, significantly reduces the proliferation, migration, and invasion of aggressive prostate cancer cells. TAK-931 treated prostate cancer cells exhibit an abnormal cell cycle profile, suggesting that CDC7 inhibition induces replication stress and promotes apoptosis. Collectively, our findings demonstrate that CDC7 is a regulator of tumor progression in prostate cancer and represents new therapeutic target in advanced prostate cancer.

The spread of antibiotic resistance through horizontal gene transfer (HGT) in food-associated bacteria represents an emerging public health concern. Staphylococcus equorum strain KS1030, isolated from a high-salt fermented food, carries plasmids encoding the lincomycin resistance gene lnuA and the relaxase gene rlx, both of which contribute to resistance dissemination. Previous studies have shown that strain KS1030 can transfer the lnuA gene both within and across subspecies when exposed to lincomycin. To investigate the transcriptional basis of this phenomenon, we performed RNA sequencing (RNA-Seq) to analyze the global gene expression profile of KS1030 under lincomycin stress (30 mg/L). Transcriptome analysis revealed more differentially expressed genes (DEGs) at 2 h than at 4 h, with enriched categories including amino acid transport and metabolism (22.9%), transcription (19.3%), and inorganic ion transport and metabolism (14.7%). Genes involved in ornithine, Fe³⁺, siderophore, and tryptophan metabolism, as well as stress regulators such as sigB, dcuSR, and helix-turn-helix transcriptional regulators, were strongly induced. Genome analysis further identified the competence (Com) operon and DNA translocase (ftsK) as potential transport systems, with comGC classified as a DEG. To capture short-term dynamics not resolved by RNA-Seq, quantitative real-time PCR was performed at 30-min intervals. Several genes, including comC, comEC, comFA, and ftsK, peaked at 1.5 h, while lnuA and rlx peaked at 1 h. Although the roles of the Com and FtsK systems in HGT remain unresolved, their induction under lincomycin stress suggests a potential contribution to plasmid transfer, offering new insight into the adaptive and gene transfer responses of S. equorum. However, as this study relies solely on transcriptional data from a single strain and antibiotic condition, functional validation-such as targeted gene disruption-will be required to confirm the involvement of these candidate HGT-related genes.

Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian cancer. Here, we found that ovarian cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian cancer, thereby counteracting platinum and PARP inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian cancer.

Lead (Pb) is a widely ubiquitous and highly toxic heavy metal pollutant that severely inhibits crop growth. However, the molecular regulatory mechanisms of Pb toxicity in plants remain incompletely understood. We investigated growth indices, chlorophyll content, and chlorophyll fluorescence parameters in rice leaves after 1 day of treatment with 100 μM Pb(NO₃)₂ stress, and performed transcriptomics analysis using RNA sequencing (RNA-seq) technology. The results indicated that Pb stress significantly reduced growth parameters, SPAD values, maximum photochemical efficiency (Fᵥ/Fₘ), and performance index (PIABS) in rice seedlings, as well as the electron transport efficiency of Photosystem II (PSII), as reflected by decreased φE₀ and ψ₀. In contrast, it markedly increased energy absorption per reaction center (ABS/RC), non-photochemical energy dissipation (DI₀/RC), and the quantum yield of dissipation (φD₀). Through RNA-seq analysis, 1721 differentially expressed genes (DEGs) were identified. Gene Ontology (GO) enrichment analysis showed that the most significantly enriched upregulated DEGs were oxidation-reduction processes. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) joint analysis identified 8 common pathways, such as cysteine and methionine metabolism, brassinosteroid biosynthesis, and photosynthesis. All DEGs in cysteine and methionine metabolism were upregulated. Additionally, Pb stress upregulated genes encoding heat shock transcription factors and heat shock proteins, whereas genes encoding MYB and WRKY were downregulated. This study systematically revealed the transcriptome response mechanisms of rice leaves under short-term Pb stress, providing crucial data support and theoretical foundations for deepening the understanding of rice response mechanisms to heavy metal stress.

Neuroinflammation is a key pathological process contributing to hippocampal neurogenesis impairment and cognitive dysfunction. This study aimed to evaluate the neuroprotective effects of α-Bisabolol (α-Bis), a natural sesquiterpene alcohol, on lipopolysaccharide (LPS)-induced neuroinflammation in mice. LPS administration decreased neural stem cell (NSC) proliferation, neural differentiation, cognitive dysfunction and increased NSC apoptosis. Oral administration of α-Bis ameliorated LPS-reduced hippocampal NSC proliferation, differentiation, cognitive function and LPS-induced NSC apoptosis. Mechanistically, α-Bis attenuated LPS-enhanced microglial activation and suppressed CD68 + cells with pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) but increased CD206+ cells with anti-inflammatory cytokines (IL-10, TGF-β) expression. In addition, α-Bis inhibited the TLR4/MAPK/NF-κB signaling cascade activated by LPS. These findings suggest that α-Bis confers neuroprotection by promoting anti-inflammatory cytokine expression from CD206+ microglia via downregulation of TLR4/MAPK/NF-κB signaling in the hippocampus under LPS-induced neuroinflammation, thereby restoring hippocampal neurogenesis and cognitive function impaired by LPS, highlighting its therapeutic potential for inflammation-associated neurodegenerative diseases.

Colorectal cancer (CRC) is one of the deadliest cancers, ranking third in cancer incidence worldwide. These tumor cells often adopt unique strategies under chemotherapeutic stress to attain a reversible drug-tolerant state and evade cell death. However, the molecular adaptations associated with this transitory emergence of the drug-tolerant state remain elusive. Herein, epigenetic alterations often dictate such reversible dynamic changes, and this study aims to characterize the role of specific epigenetic modifiers governing CRC cell survival under cisplatin exposure and their subsequent relapse. We observed that under cisplatin-stress there is a drastic increase in the histone-repressive mark-H3K27me3, linked to an enhanced expression of EZH2, driving transcriptional inhibition of cell proliferation-associated genes and a proliferative arrest. Interestingly, cisplatin-induced oxidative stress increased the expression of P65 protein, which was found to interact with and regulate EZH2 expression. Quenching of ROS, cisplatin-rescue, or P65 inactivation compromised EZH2 activity, concurrent with a re-initiation of cell proliferation. Interestingly, this reversal to proliferative state was associated with an elevated activity of the histone lysine demethylase-KDM6A. The promoter elements of the proliferative genes were now occupied by KDM6A instead of EZH2. Accordingly, a genetic knockdown or pharmacological inhibition of KDM6A in vitro not only resulted in increased cell death but also prevented emergence of the re-proliferative CRC cells. Furthermore, KDM6A inhibition in combination with cisplatin, resulted in an increased tumor regression in vivo. Our study thus highlights the importance of KDM6A as a therapeutic target in preventing CRC growth and relapse which can have future therapeutic implications.