LncRNA GAS5 regulates apoptosis in ovarian cancer cells by regulating O-GlcNAcylation of GOLGA8B.

Integrated single-cell and bulk transcriptomics reveals STAB1 as a novel therapeutic target for ovarian cancer.

Identification of DHX58 as a potential therapeutic target for ovarian cancer through multi-omics Mendelian randomization and transcriptomic data analysis.

BackgroundOvarian cancer is a lethal malignancy with limited therapeutic options, highlighting the urgent need to identify reliable biomarkers and therapeutic targets. This study investigates the clinical and oncogenic significance of β-hydroxybutyrate dehydrogenase 1 (BDH1) as a potential therapeutic target in ovarian cancer.MethodsIntegrative genomic analyses were conducted to evaluate the oncogenic potential of BDH1 by assessing its gene amplification and expression patterns in ovarian cancer. Functional assays, including BDH1 knockdown, were performed to examine its effects on proliferation, colony formation, cell cycle, and stemness. Mechanism exploration involved assessing the Wnt/β-catenin pathway. Virtual screening was used to identify BDH1 inhibitors.ResultsBDH1 was identified as a crucial oncogene in ovarian cancer progression, characterized by frequent gene amplification and overexpression, which strongly correlated with advanced disease stage and poor patient prognosis. Functionally, BDH1 promoted tumor progression by regulating G1/S transition proteins and maintaining cancer stemness via Wnt/β-catenin signaling. BDH1 depletion suppressed malignant phenotypes, confirming its oncogenic role. BDH1 was pharmacologically targeted by centrinone, which effectively downregulated oncogenic effectors.ConclusionOur study underscores BDH1 as a multifunctional oncogenic driver in ovarian cancer. The strong association of BDH1 with aggressive disease underscores its clinical relevance as a prognostic predictor, while its functional role and pharmacological inhibition position BDH1 as a promising therapeutic target for ovarian cancer.

ALKBH5, one of the RNA N6-methyladenosine (m6A) demethyltransferases, has been suggested to be involved in the progression of several cancers. The aim of this study was to investigate clinical significance and biological functions of ALKBH5 in promoting ovarian cancer progression. We found a significant upregulation of ALKBH5 expression in ovarian cancer tissues compared with normal tissues. Correlation analyses indicated an association between heightened ALKBH5 expression and FIGO stage, as well as lymph node metastasis. Importantly, increased ALKBH5 expression indicated shorter progression-free survival and overall survival. Moreover, we found that hypoxia induced an increase in ALKBH5 expression in ovarian cancer via an HIF-1α-dependent mechanism. Loss-of-function assays demonstrated that ALKBH5 knockdown inhibited ovarian cancer cell progression both in vitro and in vivo. Furthermore, we found that knockdown of ALKBH5-meidated m6A demethylation decreased Notch2 mRNA stability and expression, resulting in the inhibition of cell proliferation, invasion and metastasis in OC cells. In summary, our findings demonstrated that ALKBH5 promotes the progression of ovarian cancer by activating Notch2 signaling, and suggested that ALKBH5 functions as an oncogene and may serve as a prognostic biomarker and therapeutic target in ovarian cancer.

This study aimed to investigate the role of SLMO2 in regulating mitochondrial function and its interaction with TRIAP1, which inhibited apoptosis in ovarian cancer cells. The findings provided valuable insights into potential therapeutic targets for ovarian cancer. Lentiviral infection models were developed using SKOV3 and OVCAR3 ovarian cancer cell lines. Techniques such as flow cytometry, western blotting, immunofluorescence, and transmission electron microscopy were employed to systematically assess the regulatory effects of SLMO2 and TRIAP1 on cell proliferation, apoptosis, mitochondrial function, and autophagy. Additionally, a subcutaneous mouse tumor xenograft model was utilized to further investigate the combined effects of SLMO2 and TRIAP1 on ovarian cancer cells, with the aim of elucidating the specific mechanisms underlying tumor growth and apoptosis. SLMO2 enhanced mitochondrial function by increasing membrane potential and reducing reactive oxygen species (ROS) levels. Furthermore, through its interaction with TRIAP1, SLMO2 inhibited autophagy, which further suppressed apoptosis in ovarian cancer cells and regulated mitochondrial function. In vivo experiments showed decreased ROS levels and reduced expression of autophagy-related proteins, further supporting the roles of SLMO2 and TRIAP1 in the regulation of mitochondrial function. SLMO2 regulated mitochondrial function and inhibited apoptosis in ovarian cancer cells by interacting with TRIAP1. The combination of SLMO2 and TRIAP1 promoted tumor cell growth and induced oxidative stress, suggesting potential therapeutic targets for ovarian cancer.

Ovarian cancer (OC) remains the most lethal gynecologic malignancy, primarily due to late-stage diagnosis resulting from nonspecific early symptoms. This study aims to identify novel genetic targets and elucidate the underlying mechanisms driving OC progression by integrating multi-omics datasets. We comprehensively analyzed OC datasets from the Gene Expression Omnibus (GEO) database and applied Mendelian randomization (MR) integrating genome-wide association studies (GWAS) and expression quantitative trait locus (eQTL) data to identify OC-associated genes. Cross-analysis revealed genes co-expressed with both disease-relevant and differentially expressed genes (DEGs), followed by pathway and functional enrichment investigations. Sixteen significant genes were identified, including XPR1, SPINT1, NFE2L3, FGFRL1, SLC24A4, CDC42EP3, PAPLN, GRAMD1B, TMEM71, MAP1A, CD36, ADRA2A, MYL9, PPBP, SIGLEC11 and CMTM5. These genes predominantly regulate tumor immune cell activity, with CIBERSORT analysis revealing distinct immune cell distribution patterns in OC. Our findings provide novel insights into OC molecular mechanisms and highlight promising therapeutic targets, establishing a foundation for future research and clinical applications.

Abstract Background: Human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+ with fluorescent in situ hybridization [FISH]-negative) early breast cancer (EBC) constitutes a significant proportion of breast malignancies. Genomic instability, particularly defective DNA repair, is a recognized driver of tumorigenesis. Homologous recombination repair (HRR)-related gene mutation leading to homologous recombination deficiency (HRD) increases risks for tumorigenesis and has been proved as a viable therapeutic target in ovarian cancer and triple-negative breast cancer, with therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors and carboplatin. However, current evidence is largely derived from studies in European and American populations. Therefore, clinical research focusing on Chinese patients with HER2-low EBC is warranted. Methods: This prospective, single-center, observational study (NCT05466786) aimed to enroll 255 treatment-naïve patients with operable primary HER2-low (IHC 1+ of IHC 2+/FISH-negative) invasive EBC, who had completed HRR-related gene mutation and HRD assessments using a customized next-generation sequencing panel targeting 520 cancer-related genes. The HRD score was derived from the combined assessment of three genomic scar signatures: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions. HRD positivity was defined as an HRD score ≥42 and/or the presence of a BRCA1/2 mutation. All enrolled patients received standard therapies according to the National Comprehensive Cancer Network guidelines. The primary outcome was to characterize the landscape of HRR-related gene mutations and HRD. Results: From August 2022 to September 2025, 129 of 255 planned patients were enrolled. The median age of the patients was 43 years (range 27-68), and 38 (30%) had family history of malignant tumor. Tumors were predominantly T1-2 (112 [87%]), node-negative (74 [67%]), and stage II-III (95 [74%]); 103 (80%) were hormone receptor (HR)-positive (estrogen receptor ≥10%), and 102 (79%) had Ki67 expression ≥20%. Among HRR-related gene mutations, BRIP1 (17 [13%]), NBN (11 [9%]), PALB2 (8 [6%]), BRCA 2 (8 [6%]), BRCA 1 (6 [5%]), ATM (4 [3%]), and ATR (4 [3%]) were most common. The median HRD score was 20 (Interquartile range 10-35), and 26 (20%) patients were HRD-positive (including 14 had gBRCA1/2 mutation). HRD-positive status was significantly more common in tumors with histological grade-III, HR-negative, or Ki67 expression ≥20%. Among the 520 cancer-related genes, somatic alterations were frequently observed in PIK3CA (58 [45%]), TP53 (48 [37%]), GATA3 (34 [26%]), MYC (22 [17%]), CCND1 (21 [16%]), FGF3 (20 [16%]), FGF4 (20 [16%]), and FGF19 (20 [16%]). Recurrent germline alterations included BRCA2 (8 [6%]), BRCA1 (6 [5%]), PALB2 (5 [4%]), ATM (2 [2%]), BLM (1 [1%]), and MSH3 (1 [16%]). Conclusions: This study delineates the landscape of HRR-related gene mutation and HRD in Chinese patients with HER2-low EBC. HRD-positivity was significantly associated with histological grade III, HR-negative status, and Ki67 expression ≥20%. Further enrollment is warranted to provide a more comprehensive representation of HRR-related genomic alterations and HRD in this patient population. Citation Format: R. Hu, Y. Xia, Q. Lin, W. Zhang, J. Chen, Y. Zhu, Y. Yang, Q. Lin, Y. Quan, H. Liu, C. Gong. Landscape of homologous recombination repair-related gene mutation and homologous recombination deficiency in Chinese patients with HER2-low early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-28.

HighlightsWhat are the main findings?METTL3 expression and global m6A RNA methylation are increased following platinum treatment and in platinum-resistant ovarian cancer models.ADAM23 is identified as a METTL3-regulated, m6A-associated transcript whose expression correlates with platinum response.What is the implication of the main finding?METTL3-dependent epitranscriptomic regulation is associated with the development of platinum resistance in ovarian cancer.Pharmacologic inhibition of METTL3 enhances platinum responsiveness, supporting m6A regulation as a potential therapeutic vulnerability.N6-methyladenosine (m6A) has emerged as a pivotal regulator of post-transcriptional gene control, yet its contribution to chemotherapy resistance remains insufficiently defined. Here, we describe a previously unrecognized METTL3-ADAM23 epitranscriptomic regulatory relationship associated with platinum (Pt) resistance in ovarian cancer (OC). We show that cisplatin treatment increases global m6A levels and METTL3 expression, linking Pt exposure to activation of the m6A machinery. Functional perturbation studies demonstrate that METTL3 overexpression enhances cisplatin resistance, whereas METTL3 knockdown or pharmacologic inhibition with the selective METTL3 inhibitor STM2457 sensitizes OC cells to Pt treatment in vitro and improves Pt response in vivo. Transcriptomic profiling identifies ADAM23, a cell-adhesion-related tumor suppressor, as a METTL3-dependent, m6A-associated transcript, with altered mRNA expression observed across multiple experimental systems and several high-confidence predicted m6A sites within its transcript. Cisplatin-associated METTL3 upregulation correlates with reduced ADAM23 expression, suggesting a potential regulatory relationship that may contribute to chemoresistance. Together, these findings support a model in which METTL3-associated increases in m6A methylation are linked to Pt resistance, in part through modulation of ADAM23 expression, and highlight METTL3 as a potential therapeutic target in OC.

Ovarian cancer (OC) remains the most lethal gynecologic malignancy. Our previous work showed that WNK lysine-deficient protein kinase 2 (WNK2) promotes OC cell proliferation and migration. To clarify the molecular basis of WNK2-driven OC progression, here, we performed transcriptome sequencing to identify WNK2-regulated mRNAs and noncoding RNAs. We validated candidate targets using qRT-PCR and Western blot analyses. Functional assays, including CCK-8, colony formation, and Transwell assays, evaluated the role of POU5F1B and its capacity to rescue the effects of WNK2 knockdown. POU5F1B is a promising OC therapeutic target, mediating WNK2-driven oncogenesis in xenograft models (n = 10). Because AKT acts downstream of POU5F1B, we examined AKT phosphorylation and found that POU5F1B displayed clear oncogenic activity in OC cells. WNK2 upregulated POU5F1B mRNA and protein levels, while POU5F1B overexpression reversed the tumor-suppressive effects caused by WNK2 depletion. Mechanistically, WNK2 silencing decreased AKT phosphorylation, which POU5F1B overexpression restored. Together, these results demonstrate that WNK2 promotes OC progression by upregulating the validated oncogene POU5F1B and activating AKT signaling. These findings establish WNK2 as an oncogenic driver and a promising therapeutic target in OC.

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression, and their dysregulation is closely linked to cancer development. Ovarian cancer (OC), particularly the high-grade serous ovarian carcinoma (HGSOC) subtype, is the most lethal gynecological malignancy, primarily due to late-stage diagnosis and limited treatment options. Among the miRNAs encoded at the often amplified 8q24.3 region, miR-6850 has emerged as a potential candidate target owing to its genomic positioning inside this hotspot and its unexpectedly low expression in HGSOC tissues and cell lines. In silico investigations indicated that, despite the gain in MIR6850 copy number, its mature products, miR-6850-5p and miR-6850-3p, were expressed at low levels; notably, MIR6850 gene amplification was associated with enhanced disease-specific survival. Functional studies revealed that ectopic production of both isoforms in SKOV-3 and NIH:OVCAR3 cells inhibited proliferation, compromised clonogenic capacity, and disturbed cell cycle progression. Moreover, miR-6850 altered cell phenotype by facilitating mesenchymal-to-epithelial transition (MET), as shown by the overexpression of E-cadherin and β-catenin and the downregulation of Slug and Vimentin. It also regulated cell adhesion and migration while reducing global protein synthesis via the downregulation of the PI3K/Akt/mTOR pathway. Our results together identify miR-6850 as a tumor-suppressive miRNA in HGSOC, demonstrating its diverse anti-oncogenic actions and underscoring its potential as a prognostic biomarker and therapeutic target in ovarian cancer.

Exploring novel therapeutic targets and developing targeted therapies constitute an urgent clinical need for improving the prognosis of ovarian cancer (OC), particularly among patients with advanced stages. Currently, chimeric antigen receptor T (CAR-T) cell therapy has been demonstrated to have a remarkable therapeutic effect in hematological malignancies, while its application remains limited in OC due to the absence of appropriate target molecules and the complex immunosuppressive tumor microenvironment (TME). Poliovirus receptor (PVR, CD155) has been the subject of extensive research in the field of regulatory molecules within the immune microenvironment. However, there has been a paucity of research investigating its role in OC. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is barely expressed in normal tissues but widely expressed in tumor tissues, making it a promising target for CAR-T therapy. Nevertheless, the potential effectiveness of CAR-T cell targeting ROR1 in OC remains unknown. Therefore, the purpose of this study is twofold: The primary objective of this study is to investigate the potential efficacy of single-target ROR1-CAR-T cells on OC. The secondary objective is to examine the feasibility of CD155 as an immunotherapy target for OC and to determine whether combined targeting of CD155 can enhance the function of ROR1-CAR-T cells in OC. ROR1 and CD155 expression were detected via flow cytometry analysis. In vitro experiments were conducted to explore the regulatory effect of CD155 on OC proliferation, invasion, angiogenesis, and T cell function. ROR1-CAR, CD155-CAR, and ROR1/CD155 bispecific CAR constructs were designed and synthesized. Then, they were introduced into T cells using lentiviral particles to generate CAR-T cells. We subsequently validated the synergistic effects of CD155 in ROR1/CD155 bispecific CAR-T cells based on cytotoxic efficacy, activation, exhaustion, and differentiation status. ROR1-CAR-T cells exhibited tumoricidal activity in OC, but elevated tonic signaling was observed, resulting in rapid depletion. CD155 constitutes an ideal therapeutic target in OC: firstly, ubiquitous CD155 expression in OC cell lines. Secondly, CD155 promotes tumor proliferation, migration, and angiogenesis in OC cell lines, acting as an oncogenic driver. Thirdly, CD155 impairs T cell function and accelerates their depletion, contributing to an immunosuppressive TME. The bispecific CAR-T combined targeting CD155 and ROR1 demonstrated superior cytotoxicity compared to single-target ROR1-CAR-T or CD155-CAR-T. Co-targeting CD155 significantly attenuated tonic signaling and delayed CAR-T cell exhaustion. CD155 emerges as a promising therapeutic target for CAR-T therapy in OC. The bispecific CAR-T construct that co-targets CD155 and ROR1 demonstrates superior and durable tumoricidal activity, offering new perspectives on OC targeted therapy.

SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression.

Ovarian cancer (OC) remains the most lethal gynecologic malignancy. Our previous work showed that WNK lysine-deficient protein kinase 2 (WNK2) promotes OC cell proliferation and migration. To clarify the molecular basis of WNK2-driven OC progression, here, we performed transcriptome sequencing to identify WNK2-regulated mRNAs and noncoding RNAs. We validated candidate targets using qRT-PCR and Western blot analyses. Functional assays, including CCK-8, colony formation, and Transwell assays, evaluated the role of POU5F1B and its capacity to rescue the effects of WNK2 knockdown. POU5F1B is a promising OC therapeutic target, mediating WNK2-driven oncogenesis in xenograft models (n = 10). Because AKT acts downstream of POU5F1B, we examined AKT phosphorylation and found that POU5F1B displayed clear oncogenic activity in OC cells. WNK2 upregulated POU5F1B mRNA and protein levels, while POU5F1B overexpression reversed the tumor-suppressive effects caused by WNK2 depletion. Mechanistically, WNK2 silencing decreased AKT phosphorylation, which POU5F1B overexpression restored. Together, these results demonstrate that WNK2 promotes OC progression by upregulating the validated oncogene POU5F1B and activating AKT signaling. These findings establish WNK2 as an oncogenic driver and a promising therapeutic target in OC.

Nanoformulation of a Pin1 inhibitor potentiates the efficacy of liposomal doxorubicin in second-line therapy for ovarian cancer.

Ovarian cancer (OC) remains a leading cause of gynecological cancer–related mortality, largely due to metabolic reprogramming and aggressive progression. Zinc finger protein 280A (ZNF280A), a poorly characterized transcriptional regulator, has recently been implicated in tumorigenesis, but its mechanistic role in OC remains undefined. Here, we identify ZNF280A as an oncogenic driver that promotes OC progression through transcriptional regulation of acrosomal vesicle protein 1 (ACRV1) and activation of the PI3K/AKT signaling pathway. ZNF280A expression was markedly elevated in OC tissues and cell lines and correlated with advanced clinicopathologic features and poor patient survival. Functional assays revealed that ZNF280A knockdown inhibited OC cell proliferation, migration, and tumorigenesis while inducing apoptosis both in vitro and in vivo. Mechanistically, ZNF280A enhanced ACRV1 transcription by interacting with the transcription factor CUX2, thereby facilitating its recruitment to the ACRV1 promoter. Elevated ZNF280A or ACRV1 expression activated PI3K/AKT signaling and increased glycolytic enzyme expression (PKM2 and LDHA), glucose uptake, lactate production, ATP generation, and extracellular acidification rate, whereas pharmacological inhibition of AKT or glycolysis abrogated these effects. Collectively, our findings establish ZNF280A as a key regulator of metabolic reprogramming in OC through the CUX2–ACRV1–PI3K/AKT axis, highlighting this pathway as a potential therapeutic target in ovarian cancer.

Background: The persistent challenge of ovarian cancer as a major driver of cancer mortality in the female population stems largely from its tendency toward late-stage identification and frequent disease relapse. The cadherin (CDH) gene family, crucial for cell-cell adhesion, plays complex roles in cancer progression. Objective: Bioinformatics analysis of the CDH gene family in ovarian cancer. Using multiple public databases. Methodology: Transcriptome analysis of cadherin (CDH) gene family in ovarian cancer was performed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Prognostic value of differentially expressed CDH genes was assessed using Kaplan-Meier plotter Overall Survival (OS) . Protein-level validation was performed using Human Protein Atlas (HPA) portal which provides immunohistochemistry (IHC). By using GSCALite web server, the assessment of immune cell infiltration was conducted to explore correlations between cadherin expression and tumor immune microenvironment and drug sensitivity analysis was performed to evaluate candidate CDH genes as therapeutic response predictors. Results: Our findings revealed significant differential expression of several CDH genes: CDH1 and CDH4 were downregulated while CDH2, CDH6, CDH11, and CDH23 were upregulated in ovarian cancer tissues. Survival analysis identified CDH6, CDH11, and CDH23 as adverse prognostic markers correlating with poorer overall and progression-free survival, while high CDH2 and CDH4 expression associated with improved survival. Genetic alteration analysis revealed diverse genomic changes across the CDH family, with protein expression data largely corroborating transcriptomic findings. Novel associations between CDH expression and drug sensitivity emerged as potential predictive biomarkers. CDH1 and CDH11 expression correlated with Paclitaxel and Dasatinib resistance, respectively, while CDH2 and CDH6 expression indicated sensitivity to PI3K and Src kinase inhibitors. Conclusion: This study provides comprehensive molecular characterization of CDH family roles in ovarian cancer progression, prognosis, drug response, and immune regulation, establishing specific CDH members as potential diagnostic and therapeutic targets for ovarian cancer.

The c-Met gene encodes a protein known as the hepatocyte growth factor receptor (HGFR), which is frequently called the c-Met receptor. This gene and its encoded receptor play pivotal roles in normal physiological processes as well as in the initiation, progression, and metastasis of various diseases, particularly cancer. However, the precise molecular mechanisms underlying the missense mutation at residue 110 (valine to isoleucine) within this gene remain unexplored. This mutation occurs hypothesized to impact protein stability; yet, how it alters the three-dimensional structure, dynamic behavior, and functional properties of c-Met is unclear. In this study, we innovatively integrate high-precision structure prediction, protein model-based molecular dynamics simulations, and AI-driven thermodynamic stability analyses to systematically elucidate the molecular mechanism by which the residue 110 mutation disrupts protein structural integrity, modulates conformational dynamics, and ultimately impairs receptor function. Utilizing c-Met as a tumor-associated antigen, we developed a PD-1 antibody-secreting c-Met-targeted CAR-T cell and evaluated its cytotoxic efficacy against the serous ovarian cancer cell line SKOV-3 both in vitro and in vivo. This study reveals that mutation at position 110 of c-Met induces protein conformational reprogramming, transforming it from a stable, compact structural state into a more loosely organised and dynamically flexible conformation. Experimental evidence confirms that this structural alteration leads to significantly elevated protein expression levels of the V110I mutant in ovarian cancer cells compared to the wild-type, functionally demonstrating the substantive impact of altered conformational stability on protein metabolism. Building upon the identification of c-Met protein as a potential therapeutic target in ovarian cancer, we developed c-Met CAR-T cells capable of secreting anti-PD-1 antibodies. These cells exhibited markedly enhanced cytotoxicity against tumour cells overexpressing c-Met, accompanied by increased release of key effector cytokines such as interferon-γ. This research framework offers a precise, synergistic therapeutic strategy to overcome limitations in CAR-T therapy response within serous ovarian carcinoma.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13048-025-01903-z.

Ovarian cancer (OC), a common gynecological malignancy, seriously threatens the lives and health of women. Though several serological markers are used for the early diagnosis of OC, most have low specificity and sensitivity. Micro-RNAs (miRNAs), a family of non-coding RNAs that function at the post-transcriptional level, are emerging as specific biomarkers to achieve effective diagnosis and treatment strategies for OC. In this review, we summarize the current investigations on miRNAs in the detection and monitoring of OC and discuss the molecular mechanisms that may provide a reliable detection method for OC at early stages. Thus, miRNAs are promising biomarkers, suggesting their potential as therapeutic targets in OC.

Ovarian cancer represents one of the most prevalent gynecological malignancies with a poor prognosis. Targeting glycolytic pathways has emerged as a novel cancer therapeutic strategy. N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification plays a regulatory role in cancer glycolysis. Phosphoglycerate mutase 1 (PGAM1) functions as a critical glycolytic enzyme and potential therapeutic target in oncology. This study investigated the functional role and underlying mechanisms of NAT10 in ovarian cancer progression. Cellular glycolysis was assessed through glucose uptake measurements, lactate production quantification, and extracellular acidification rate analysis. Cell stemness characteristics were evaluated using sphere formation assays and western blot analysis. Molecular mechanisms were explored via quantitative real-time PCR, RNA immunoprecipitation (RIP), ac4C-specific RIP, dot blot analysis, and dual-luciferase reporter assays. Elevated NAT10 expression and ac4C modification levels were observed in ovarian cancer cells. NAT10 silencing significantly inhibited both cell stemness properties and glycolytic activity. Mechanistically, NAT10 enhanced PGAM1 mRNA stability through ac4C modification. Re-expression of PGAM1 reversed the functional effects induced by NAT10 depletion in ovarian cancer cells. Furthermore, in vivo tumor growth experiments demonstrated that NAT10 promotes tumorigenesis. Our findings demonstrate that NAT10 facilitates ovarian cancer progression by mediating ac4C modification of PGAM1. This study identifies a novel and potentially effective therapeutic target for ovarian cancer treatment.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-22902-6.