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Lung cancer is one of the most common malignancies and the leading cause of cancer-related mortality worldwide, posing a major public health challenge. Flavonoids, a large and diverse group of plant metabolites, exhibit various anticancer properties, making them promising candidates for therapeutic applications. This study evaluated the anticancer efficacy of methoxy flavonoids and elucidated their underlying mechanisms of action in A549 lung cancer cells. A549 cells were treated with various flavonoids (AKC1-AKC5), and their effects were analyzed using an MTT assay, DAPI staining, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, colony formation, and wound scratch tests. Molecular docking was also performed to confirm the binding of AKC1 and AKC3 to EGFR, BCL-2, and CDK-2 proteins. AKC1 and AKC3 prevented the growth of A549 lung cancer cells with IC50 of 64.57 and 19.80 μM among 5 methoxy flavonoids. AKC1 and AKC3 triggered notable alterations in the shape and reduced the colony-forming potential of A549 cells. The DAPI staining experiment demonstrated that AKC1 and AKC3 impede the growth of cancer cells through activation of apoptotic cell death. Moreover, the anticancer properties of AKC1 and AKC3 were attributed to significant inhibition of MMP and a notable ROS enhancement in a dose-related pattern. The wound scratch assay demonstrated that AKC1 and AKC3 suppressed A549 lung cancer cell migration, suggesting their anti-metastatic properties. Molecular docking studies confirmed that AKC-1 and AKC-3 bind strongly to EGFR, BCL-2, and CDK2, suggesting a multi-target mechanism that underlies their anti-proliferative and pro-apoptotic effects in A549 cells. AKC1 and AKC3 exhibited significant anticancer activity against A549 cells and may serve as promising therapeutic drugs for lung cancer treatment.

Identifying robust biomarkers for early cancer detection remains challenging, particularly when working with limited or heterogeneous datasets. Here, we present a proof-of-concept deep learning framework for cancer classification using blood-based proteomic profiles. Our approach leverages sample type transfer and synthetic data augmentation to improve performance and generalization across sample types. Models were trained on plasma proteome data from 13,208 pan-cancer cases and 39,806 controls in the UK Biobank. To address class imbalance and enrich the feature space, a convolutional neural network (CNN-Synth) was trained to detect cancer cases using data augmented with synthetic pan-cancer samples generated via a variational autoencoder. Performance was evaluated in an independent saliva-based dataset from a head and neck cancer case-control study (n = 156). CNN-Synth (AUC = 0.88) surpassed models trained without synthetic data (AUC ≤ 0.77). SHapley Additive explanations identified well-known cancer markers as key features. These results highlight the use of sample type transfer and synthetic data augmentation, with further validation needed.

Monoclonal antibody-based therapies have substantially improved outcomes in breast cancer, particularly through HER2-directed treatment strategies, but have also introduced important cardiovascular toxicities that require careful recognition and management. This narrative review summarizes current evidence on cardiotoxicity associated with monoclonal antibody therapies used in breast cancer, with emphasis on HER2-targeted antibodies, antibody-drug conjugates, and selected immune checkpoint inhibitors.Trastuzumab remains the best-characterized monoclonal antibody associated with cancer therapy-related cardiac dysfunction, most commonly presenting as left ventricular systolic dysfunction, particularly in patients previously exposed to anthracyclines or with baseline cardiovascular risk factors. Pertuzumab and currently available antibody-drug conjugates have not shown a major increase in cardiotoxic risk beyond that observed with established HER2-directed therapy, although long-term data remain limited for some newer agents. Immune checkpoint inhibitors are less commonly associated with cardiovascular toxicity, but may rarely cause severe immune-mediated complications, particularly myocarditis and also non-immune mediated toxicity such as cardiac dysfunction.Contemporary evaluation of cardiotoxicity increasingly relies on an integrated cardio-oncology framework incorporating left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers, with growing recognition of subclinical dysfunction and right ventricular involvement. Current management strategies emphasize baseline cardiovascular risk assessment, risk-adapted surveillance, early initiation of heart failure therapy when indicated, and individualized multidisciplinary decision-making regarding continuation of anticancer treatment, including permissive cardiotoxicity in selected patients.As the use of monoclonal antibody therapies continues to expand, optimizing the balance between oncologic efficacy and cardiovascular safety remains a central goal of modern breast cancer care.

Artificial intelligence (AI) offers a potential solution to radiologist shortages in breast cancer screening while maintaining diagnostic accuracy. Retrospective studies suggest AI performs comparably to human readers in detecting cancers, but no economic evaluations have yet used prospective trial data. We developed a de novo discrete-event simulation model to estimate the cost-effectiveness of integrating AI into the NHS screening pathway using evidence from a large prospective trial. The AI-only strategy generated a small incremental QALY gain of 0.00009 and reduced lifetime costs by £159.55 per woman invited, and had a 100% probability of being most cost-effective at the £20,000/QALY threshold. Replacing one human reader with AI also increased QALYs, by 0.00019, and reduced costs by £31.07. Triple reading (two humans plus AI) produced the largest QALY gain (0.00023) but increased costs by £72.79. All AI-based pathways reduced cancer deaths, shifted cancers from advanced (TNM stage 4) to earlier stages at detection, and increased the proportion of cancers detected by screening. Using AI in place of human readers is likely to be cost-effective, marginally improving health outcomes while reducing overall costs, with full replacement of both human readers being the most cost-effective screening strategy.

The synergistic use of silver nanoparticles (AgNPs) and photosensitizer's offers promise biomedical improvements. This study assesses and creates the potential for photosensitizers (Chlorine e6 (Ce6), Methylene Blue (MB)) and Silver Nanoparticles to work together to enhance biological activity. AgNPs were created by the laser ablation method and characterized using methods including scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD).The antibacterial and anticancer properties of these nanoparticles, both individually and in combination with photosensitizers, were further examined. AgNPs were combined with Methylene Blue and Chlorine e6 to enhance their antibacterial activity against Gram-negative bacteria, such as Salmonella enteritidis, Pseudomonas aeruginosa, and Acinetobacter baumannii, resulting in inhibition zones of up to as large as 0.66 ± 057 mm. The anticancer properties of the combination therapy were also examined against MCF-7 breast cancer cells, where Chlorine e6 alone had an IC50 of approximately 231.2%. Another photosensitizer, Methylene blue, showed a dose-dependent reduction in cell viability, with an IC50 of around 6.52 ± 3.26%. When AgNPs and Methylene Blue combined, the IC50 decreased to 11.42 ± 5.71, indicating a synergistic increase in cytotoxicity. Similarly, Chlorine e6 and AgNPs together significantly decreased the IC50 to 80µM to 100 µM. These findings show that the combined use of Methylene Blue or Chlorine e6 with AgNPs greatly improves anticancer and antibacterial efficacy compared to their individual applications. This research highlights how AgNPs and photosensitizers have the ability to change treatment approaches by providing improved specificity and efficacy in biomedical applications.

cGAS-STING signaling can promote antitumor immunity, and tumor cell STING is suppressed in a variety of cancer subtypes that resist immune checkpoint blockade. Although STING agonists have failed clinical trials, precision approaches targeting restoration of tumor cell STING expression have yet to be explored. Here, we report that head and neck squamous cell cancer (HNSCC) exhibits a mechanism of STING suppression related to upregulation of protein tyrosine phosphatase non-receptor (PTPN) type 2 (PTPN2) that is also evident in other cancers. PTPN2 inhibition (PTPN2i) increases HNSCC tumor cell STING by restoring IFNγ-STAT1-mediated induction of STING mRNA. This restores sensitivity to STING agonism and natural killer cell activation, suppressing tumor growth in an immune cell-dependent manner in anti-PD-1 refractory syngeneic HNSCC mouse tumor models in female mice. Together, these findings demonstrate that PTPN2i can unleash STING agonist response, providing a rationale for the evaluation of this therapeutic combination in HNSCC and potentially other cancer types.

Cisplatin resistance limits the effectiveness of ovarian cancer (OC) therapy. Arvanil is a synthetic capsaicin derivative with favorable pharmacokinetic properties. This study showed that Arvanil enhances the anti-tumor effect of cisplatin in cisplatin-resistant ovarian cancer cells, partly associated with HMOX1-related ferroptosis. The combination treatment elevated reactive oxygen species (ROS), lipid peroxidation (LPO), and ferrous ion (Fe²⁺) levels, suppressed GPX4 protein expression, and activated multiple key ferroptosis regulators. Inhibition of HMOX1 partially reversed these effects, confirming its pivotal regulatory role. In vivo experiments further validated the synergistic anti-tumor efficacy of the Arvanil-cisplatin combination, with no significant changes in body weight and no apparent histopathological or serum biochemical abnormalities detected under the tested conditions. This study provides a novel strategy to overcome cisplatin resistance and expands the potential application of small-molecule ferroptosis inducers in cancer therapy.

This study evaluated the polyphenol content of leaf extracts from Artemisia monosperma (AM) and investigated their antioxidant properties, cytotoxic effects, and potential to induce DNA damage in human cancer cell lines. High-performance liquid chromatography (HPLC) quantified polyphenols in methanolic (AMM), ethanolic (AME), and aqueous (AMA) extracts, identifying 13 compounds in AME and 12 in AMA. AMM exhibited the strongest antioxidant activity (IC50 = 24 µg/ml). Both AME and AMM demonstrated potent anticancer activity against HCT-116 (IC₅₀ = 0.38 µg/mL for AMM) and HUH-7 (IC₅₀ = 21.95 µg/mL for AMM) cells, while exhibiting minimal cytotoxicity toward normal skin fibroblast cells (BJ-1; IC₅₀ = 13.05 µg/mL for AMM), with AMM demonstrating particular selectivity for HCT-116 cells. AMM induced DNA fragmentation and modulated apoptosis-related gene expression (Bax, Bcl-2, p53) in HUH-7 cells and caused cell cycle arrest at G0/G1 phase in HCT-116 cells. Molecular docking further supported AMM's apoptosis activity. These results position A. monosperma as a rich source of bioactive polyphenols and antioxidants, with AMM showing promise as a therapeutic agent, especially for colorectal cancer.

Physical performance impairments are common in cancer survivors and can limit daily activities, quality of life, and long-term health. Although structured exercise programs have proven beneficial for improving physical performance, maintenance of these benefits is unclear. This study aimed to systematically evaluate whether improvements in physical performance are maintained following structured exercise oncology interventions. A systematic search was conducted for randomized controlled trials (RCTs) published between January 1990 and March 2025. Eligible trials engaged adult cancer survivors in structured exercise interventions and reported objective measures of cardiorespiratory fitness, muscular strength, and/or walking capacity at the end of the intervention and ≥ 3 months after program completion. Data were pooled using random-effects meta-analyses with weighted mean differences (WMD) used to summarize effects. Twenty-four RCTs (2289 participants; mean follow-up post-intervention = 8 months) were included. Exercise significantly improved cardiorespiratory fitness at post-intervention (WMD =  + 1.76 ml/kg/min; p = 0.008); however, improvements were attenuated at follow-up (WMD =  + 1.24 ml/kg/min; p = 0.130). Similarly, upper and lower body strength improved post-intervention (WMD = + 3.35 kg; p = 0.001; WMD =  + 12.7 kg; p = 0.045), but effects diminished at follow-up (WMD =  + 1.80 kg; p = 0.081; WMD =  + 10.0 kg; p = 0.093). In contrast, walking capacity increased post-intervention (WMD = + 40.3 m; p = 0.002) and remained elevated at follow-up (WMD =  + 49.4 m; p = 0.006). Certainty of evidence ranged from very low to low across outcomes, primarily due to risk of bias, inconsistency, and imprecision in effect estimates. Structured exercise interventions were found to produce short-term improvements in physical performance among cancer survivors. Although gains in cardiorespiratory fitness and muscular strength appeared to persist at follow-up, they were attenuated compared with post-intervention and supported by very low certainty evidence. In contrast, walking capacity demonstrated sustained improvements at follow-up, though the certainty of evidence remained low. Future work is needed to identify longer-term effects (> 12 months) and develop strategies to better maintain improved physical performance. While exercise programs can improve physical performance, these benefits may not persist without ongoing support. Cancer survivors should be encouraged to continue self-directed exercise after program completion, and exercise programs should incorporate strategies to maintain longer-term improvements in physical performance.

Ovarian cancer (OC) remains the most lethal malignancy within the spectrum of gynecological cancers globally. While protein S-palmitoylation has been extensively implicated in tumor progression, its specific functional contributions and molecular mechanisms in the context of OC pathogenesis remain to be fully elucidated. This article aims to explore the prognostic effect associated with palmitoylation in OC. In this study, palmitoylation-related genes (PRGs) were defined as genes encoding enzymes directly involved in the palmitoylation/depalmitoylation process, as well as genes whose functions, subcellular localization, or signaling are regulated by this modification. Based on this definition, PRGs comprising enzymes and regulated substrates, were identified from public transcriptomic databases. By intersecting ovarian cancer (OC)-associated and palmitoylation-linked differentially expressed genes (DEGs), candidate targets were pinpointed. A prognostic risk model was then constructed using LASSO and Cox regression analyses on the TCGA-OV cohort (N&#x2009;=&#x2009;378) and validated in the GSE51088 cohort (N&#x2009;=&#x2009;152). This model was integrated into a predictive nomogram and further characterized through pathway enrichment, immune infiltration, checkpoint analysis, drug screening, and mutation profiling. Finally, identified markers were validated via RT-qPCR in clinical samples. Through intersecting DEGs1 and DEGs2, we obtained 24 candidate biomarkers. Four PRGs (HSPG2, BRD4, RARRES1, and SCGB1D2) were identified to construct a prognostic risk model. The risk score, alongside ethnicity and tumor stage, served as an independent prognostic indicator, integrated into a robust nomogram. Mechanistically, high-risk cohorts were characterized by dysregulated ribosome and translation initiation pathways, altered infiltration of seven immune cell types, and significant variations in seven checkpoints (e.g., CTLA4, CD274). Additionally, the model predicted sensitivities for 131 drugs and captured a high TP53 mutation rate. RT-qPCR validation confirmed the upregulation of HSPG2, SCGB1D2, and BRD4, and the downregulation of RARRES1 in OC tissues, showing high consistency with bioinformatic predictions (P&#x2009;<&#x2009;0.05). This study identified HSPG2, BRD4, RARRES1, and SCGB1D2, which served as prognostic markers reflecting the palmitoylation-related biological landscape in OC that could lay the foundation for innovative therapeutic strategies.

Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome characterized by progressive loss of fat and lean mass, systemic inflammation, and poor therapeutic responsiveness. While brown adipose tissue (BAT) is traditionally considered a protective, energy-dissipating organ, its qualitative remodeling in CAC remains poorly characterized.Here, we demonstrate that CAC induces a senescent conversion of BAT, marked by thermogenic failure, fibrosis, inflammation, and acquisition of a senescence-associated secretory phenotype (SASP). Through integrative transcriptomic, proteomic, and secretomic analyses in a murine model of lung cancer-induced cachexia, we identify S100A9 as a key factor selectively upregulated and secreted by brown adipocytes. Functional assays reveal that the BAT secretome exerts deleterious paracrine effects on white adipocytes and skeletal myotubes, promoting lipolysis and atrophy, while also impairing brown adipocyte identity in an autocrine manner. Co-culture and gain-of-function experiments with S100A9 recapitulate these phenotypes in vitro in mouse and human brown adipocytes, whereas pharmacological blockade of S100A9 signaling partially restores thermogenic and metabolic features. Collectively, our findings reveal that BAT undergoes functional reprogramming into a senescent and secretory tissue in cancer cachexia, with adipocyte-derived S100A9 acting as a novel pro-cachectic mediator. This work redefines the role of BAT in CAC and identifies S100A9 as a potential therapeutic target within the adipose-muscle crosstalk.

The RxPONDER trial established that adjuvant chemotherapy does not confer survival benefit in postmenopausal women with hormone receptor-positive (HR+)/HER2-negative breast cancer, 1-3 positive lymph nodes, and a low 21-gene Recurrence Score (RS&#x2009;&#x2264;&#x2009;25). Whether these findings have been adopted in routine clinical practice in Asian populations remains unclear. We conducted a multicentre retrospective cohort study of postmenopausal Chinese patients with HR+/HER2-breast cancer and limited nodal involvement who underwent surgical treatment and Oncotype DX testing between 2017 and 2023. Among 385 eligible patients, 54.8% had an RS&#x2009;&#x2264;&#x2009;25, yet 46.4% of this low-genomic-risk group received adjuvant chemotherapy. Chemotherapy use declined substantially following publication of RxPONDER, indicating a marked shift in treatment patterns. Importantly, no disease-free survival (DFS) benefit was observed with chemotherapy in patients with RS&#x2009;&#x2264;&#x2009;25. Multivariable analyses revealed that higher nodal burden, high histologic grade, and low progesterone receptor expression independently influenced chemotherapy decision-making despite low genomic risk. These real-world data provide supportive evidence consistent with the RxPONDER findings in a Chinese population; however, given the relatively short follow-up duration, longer-term outcomes are warranted to further substantiate these observations.

Breast cancer patients often experience significant psychological distress. This study examined distress trajectories from diagnosis to 6&#xa0;months post-treatment and explored differences across demographic, medical, and psychosocial subgroups. In this prospective cohort study, 528 patients with breast cancer were recruited between 1 December 2023 and 31 December 2024. Assessments were conducted at baseline (at diagnosis, T0), after the first treatment (T1), mid-treatment (T2), at treatment completion (T3), and at three (T4) and six months (T5) post-treatment. Growth mixture modeling (GMM) was used to identify distinct trajectories of psychological distress. Multinomial logistic regression analysis was performed to examine associations between patient-related factors and trajectory membership. Three psychological distress trajectories were identified: a high-distress remission group (17.05%), a moderate-stable distress group (11.93%), and a low-fluctuating distress group (71.02%). Multivariable analyses showed that higher educational attainment, breast-conserving surgery, early disease stage, partial self-management ability, and strong social support were associated with membership in the moderate-stable or low-fluctuating groups (p&#xa0;<&#xa0;0.05). Employment, health insurance coverage, avoidant medical coping style, and higher baseline anxiety and depression scores were concurrently associated with membership in the high-distress remission group (p&#xa0;<&#xa0;0.05). Although psychological distress generally decreased over time, 71.02% of patients followed a low-fluctuating trajectory, 11.93% maintained moderate distress with potential risk of persistence, and 17.05% showed high initial distress that remitted substantially within 6&#xa0;months. Continuous monitoring and early psychosocial support are recommended, particularly for patients with moderate- or high-risk trajectories.

Lactate, an energy source and metabolic by-product, has been implicated in cancer progression, but its role in colorectal cancer (CRC) remains incompletely understood. This study investigated the clinical significance, biological effects, and transcriptomic responses of CRC cells to lactate. In human CRC specimens, lactate levels were positively associated with advanced clinical stage and poorer disease-free survival. Functional assays showed that lactate promoted malignant cellular behaviors in both SW480 and HCT116 cells, while pH-control experiments suggested that these effects were not merely due to extracellular acidification alone. RNA sequencing in SW480 cells identified 1,418 differentially expressed genes after lactate treatment. GO and KEGG analyses revealed alterations in multiple metabolic and signaling pathways. qRT-PCR validated the alterations of representative genes, including HK2, VEGFA, JUNB, CCNB1, MAPK4, and COX2. In addition, flow cytometry showed activation of NF-&#x3ba;B and HIF-1&#x3b1; signaling following lactate treatment, and pharmacological inhibition of either pathway significantly attenuated the lactate-induced malignant phenotypes. Together, these findings provide transcriptomic and functional evidence that lactate promotes malignant phenotypes in CRC cells and offer exploratory mechanistic insights into the involvement of NF-&#x3ba;B and HIF-1&#x3b1; signaling.

Gastric cancer (GC) poses a significant health threat, and alterations in Fatty acid &#x3b2;-oxidation (FAO) may influence its progression. However, the precise mechanisms underlying this association remain unclear. FAO-related genes were analyzed using transcriptomic datasets from databases of GEO and TCGA. Totally 160 FAO-associated genes were identified, and a risk scoring model was subsequently established to stratify patients into groups of low- and high-risk. Immune characteristics, drug sensitivities, and hub genes, including IL-6, were assessed. Subsequently, immunoblotting and immunohistochemistry were performed on GC cell lines and tissue samples to evaluate IL-6 expression. Analysis of the TCGA and GEO databases revealed a FAO-related gene signature comprising ACADS, ACO2, CPT2, SLC22A5, AOC3, CD36, CIDEA, G0S2, GABARAPL1, and SERINC1. We also examined gene mutations and constructed a prognostic risk scoring model with validation achieved through a nomogram to predict gastric cancer risk. Immune infiltration analysis and drug sensitivity testing (e.g. AG-014699, Axitinib, BX-795, and Cisplatin) were also conducted. IL-6 emerged as a core gene with significant expression difference across cellular and tissue levels. FAO plays a critical role in the prognosis of GC, and IL-6 may serve as a key biomarker for diagnosis and therapeutic strategies.

Lung cancer diagnosis poses a significant clinical challenge, with emphasis on enhancing the positivity rate and accuracy of early detection. The use of bronchoalveolar lavage fluid (BALF) for detecting the methylation of ras-association domain family member 1&#xa0;A (RASSF1A) and short stature homeobox 2 (SHOX2) genes has emerged as a novel molecular diagnostic technique for lung cancer. Nonetheless, this method's positivity rate can vary due to factors such as BALF quality, and its diagnostic consistency is uncertain. It was a prospective diagnostic study with randomized sampling. In this study, 310 patients with lung lesions detected by computed tomography (CT) imaging were enrolled, and they were randomized 1:1 into pre-biopsy BALF group and post-biopsy BALF group. RASSF1A and SHOX2 methylation in BALF were detected, and CT images and tumor markers of patients were collected to develop a multimodal model based on BALF methylation for predicting malignant lung lesions. An internal validation set was employed to gauge the model's effectiveness. The findings revealed a statistically significant increase in gene methylation positivity rate and pathological cytology rates in the post-biopsy BALF group compared to the pre-biopsy BALF group (P&#x2009;<&#x2009;0.05). The model demonstrated an area under the curve (AUC) of 0.985 for predicting malignant lung masses and 0.903 for lung nodules in the training set. When tested on the validation set, the AUC for predicting malignant lung masses and lung nodules was 0.930 and 0.811, respectively. The multimodal prediction model constructed based on RASSF1A and SHOX2 methylation of post-biopsy BALF demonstrates a high predictive value for identifying malignant lung lesions.

To evaluate the efficacy of triplet chemotherapy (gemcitabine, cisplatin, and nab-paclitaxel) to the standard of care in locally advanced or metastatic gall bladder cancer. A total of 60 patients with locally advanced (unresectable) and metastatic gall bladder cancer were randomized to either of the 2 arms. Arm A received two drugs gemcitabine and cisplatin and arm B received three drugs gemcitabine, cisplatin and nab-paclitaxel. The evaluation was done post 3 and 6 cycles of chemotherapy. Patients were then followed up every 6 months for 2 years to assess response rates (RR), progression-free survival (PFS), and overall survival (OS). The combination of gemcitabine and cisplatin (arm A) had an overall response rate of 13.3% whereas it was 61.9% in patients who received gemcitabine, cisplatin, and nab-paclitaxel (0.004). The median progression-free survival for patients who received gemcitabine and cisplatin was 4.5 months (95% CI, 4.0-4.9) compared to 7.6 months (95% CI, 3.9-11.2) for patients treated with gemcitabine, cisplatin, and nab-paclitaxel (p&#x2009;&#x2264;&#x2009;0.05). There was no increase in grade 3 adverse events with the addition of nab-paclitaxel. This study showed promising results, with triplet chemotherapy having a significantly better overall response rate and median progression-free survival.

With the advent of the immunotherapy era, the combination of radiotherapy and immunotherapy has become a critical strategy to enhance patient outcomes. In addition to its direct cytotoxicity, radiotherapy modulates the immune response within the tumor and its surrounding microenvironment by stimulating the body's anti-tumor immune response. This interplay provides the rationale for combining radiotherapy with immunotherapy. This review will summarize the immunomodulatory mechanisms of radiation therapy, evaluate the clinical efficacy and safety of combining radiotherapy with immunotherapy, and outline its current applications, challenges, and future potential. In the future, the combination of radiotherapy and immunotherapy holds immense potential in esophageal cancer treatment. Through additional prospective clinical trials exploring optimal combinations, timing, and biomarkers, we can further refine treatment strategies and enhance patient survival.

Accumulating evidence demonstrates that the silencing of tumor suppressor genes by aberrant DNA methylation contributes to the initiation and progression of ovarian cancer (OC), while the systemic methylation profile and the key driver methylation events need to be further explored. Here, by analysing public databases and our resources, we identified the hypermethylation of ZNF154 promoter as a key driver of OC malignancy, which was mediated by the DNA methyltransferase complex DNMT1/UHRF1. Using CRISPR/dCas9-TET1CD, a tool for targeted demethylation, we successfully decreased the methylation level of ZNF154 promoter and reactivated ZNF154 expression, which in turn inhibited the proliferation, migration, and invasion of OC cells. Mechanistically, ZNF154 interacted with KAP1 and directly bound to the ROMO1 promoter, transcriptionally repressing ROMO1 expression, thereby reducing MMP2 and phosphorylated ERK to impede OC progression. Clinically, ZNF154 hypermethylation was correlated with its reduced expression and poor prognosis in OC patients. These findings underscore a pivotal role of aberrant ZNF154 methylation in OC pathogenesis and highlight its potential as both a therapeutic target and a prognostic biomarker for OC patients.