Original research publications

Conventional static liquid crystal (LC) biosensors are frequently constrained by limited optical contrast and insufficient sensitivity for trace biomarker detection. Here, we report a label-free biosensing platform based on dual-frequency liquid crystals (DFLCs) operated in the dynamic scattering mode (DSM). By driving the DFLC system at the crossover frequency of 22.2 kHz and an optimized voltage of 22.5 V, it entered an electrohydrodynamically unstable state, where minute interfacial perturbations induced by biomolecular recognition were amplified into high-contrast macroscopic scattering responses. Using haze as a quantitative readout, the DSM optical response stabilized within 3 s of electric-field application, and the platform achieved a limit of detection (LOD) of 0.11 ng/mL for bovine serum albumin, 0.82 and 4.86 ng/mL for cancer antigen 125 (CA125) in deionized water and human serum, respectively, demonstrating high sensitivity and robust resistance to matrix interference. To enable automated quantitative analysis and concentration prediction from the highly complex DSM optical textures, we implemented a ResNet-34-based convolutional neural network (CNN), which utilizes a residual backbone for hierarchical feature extraction from polarized optical microscopy images, integrated with a custom regression head. The deep learning model achieved a cross-validation coefficient of determination R 2 of 0.84, and 82% of the independent blind-evaluation samples were correctly assigned to their experimentally prepared concentration groups. The integration of DSM-based signal amplification with AI-driven quantitative analysis positions the DFLC biosensor as a rapid, sensitive, and automated analytical platform with strong potential for next-generation in vitro diagnostics.

Breast cancer is one of the most prevalent malignant tumors affecting women worldwide and poses a serious threat to women's health and survival. Accordingly, the development of effective technologies for breast cancer treatment has received considerable attention in biomedicine and materials chemistry. Here, push-pull electronic and heavy-atom effects were incorporated into photosensitizer design. Methoxytriphenylamine was used as an electron donor to strengthen electron-donating capability, whereas the benzothiazolium cation served as an electron acceptor. By replacing the S atom in the electron acceptor with a Se atom, four NIR-II merocyanine photosensitizers, namely S-672, S-732, Se-720, and Se-780, were synthesized. All four compounds were classified as Type I photosensitizers. The introduction of Se markedly enhanced •OH generation, and the overall ROS generation efficiency followed the order: Se-780 > Se-720 > S-732 > S-672. Cellular experiments showed that Se-720 and Se-780 exhibited low cytotoxicity under dark conditions and specifically targeted mitochondria. Upon light irradiation, Se-720 and Se-780 showed superior PDT efficacy by damaging mitochondria and triggering immune responses. Nanoparticles prepared by encapsulating Se-780 with Pluronic F127 enabled targeted NIR-II fluorescence imaging of breast tumors in mice and effectively inhibited tumor growth.

Aberrant DNA methylation in circulating cell-free DNA (cfDNA) represents a critical epigenetic biomarker for noninvasive diagnosis of ovarian cancer. However, conventional methodologies are inherently limited by the destructive nature of bisulfite conversion and the operational complexities of PCR thermal cycling. Herein, we report a bisulfite-free and PCR-free electrochemical nanochannel biosensor that modulates nanoconfined space charge to directly translate discrete epigenetic marks into measurable ion flux. Specifically, rigid DNA tetrahedrons (TDs) are covalently assembled onto anodic aluminum oxide (AAO) nanochannels, providing a sterically unhindered interface for highly efficient cfDNA capture. Target discrimination is achieved via HhaI endonuclease, which selectively cleaves unmethylated cfDNA (UME) while leaving methylated cfDNA (ME) structurally intact due to methylation-induced steric hindrance. The retained ME targets subsequently initiate an in situ hybridization chain reaction (HCR) cascade. Through this isothermal assembly, densely packed polyanionic DNA networks form at the outer surface of the nanochannels, reshaping the local electrostatic field into a high-density negative space-charge layer. This designed space charge enriches cations and reduces the access resistance, yielding a significantly amplified transmembrane ion current. Benefiting from this dual-amplified transduction mechanism, the biosensor achieves a limit of detection of 208 aM with high specificity. Furthermore, this platform successfully discriminated ovarian cancer patients from those with benign gynecological diseases using clinical plasma samples, demonstrating great translational potential for precise epigenetic liquid biopsy.

Ovarian cancer (OC) remains one of the most lethal malignancies among women due to late-stage diagnosis and limited therapeutic options. The discovery of novel, effective treatments is crucial to improving patient outcomes. Flavonoids, a diverse group of polyphenolic compounds found abundantly in fruits, vegetables, and medicinal plants, have garnered significant attention for their anticancer properties, including their potential role in ovarian cancer treatment. This comprehensive review explores the molecular mechanisms underlying the anticancer effects of flavonoids in OC, highlighting their ability to modulate key signaling pathways involved in cell proliferation, apoptosis, invasion, and metastasis. Flavonoids exert their effects through antioxidant activity, inhibition of angiogenesis, and regulation of tumor suppressor genes and growth factors. Additionally, they interact with cellular signaling molecules such as the PI3K/Akt/mTOR, MAPK, and NF-κB pathways, influencing cell survival and death. Notably, flavonoids also enhance the cytotoxicity of chemotherapeutic agents, making them valuable adjuncts in OC therapy. This review further discusses the pharmacokinetics, bioavailability, and potential challenges in the clinical application of flavonoids as therapeutic agents for ovarian cancer. The findings suggest that flavonoids, due to their multifaceted mechanisms of action and relatively low toxicity, hold promise as adjunct or alternative therapies in the treatment of ovarian cancer. Future clinical trials are essential to validate their efficacy and safety in human OC patients.

Several biomarkers play a role in treatment selection for epithelial ovarian cancer. Homologous recombination deficiency (HRD) is a biomarker reflecting predisposing germline genetic changes as well as somatically acquired changes. Tumors with HRD may be eligible for poly-ADP(ribose) polymerase inhibitor therapy in the maintenance or recurrent setting. Expression of HER2 (ERBB2 gene product) or folate receptor alpha (FOLR1 gene product), assessed using immunohistochemical assays, is a biomarker for therapy with antibody-drug conjugates. Although the biomarker landscape in ovarian cancer remains relatively limited, these markers provide meaningful diagnostic and therapeutic guidance.

Cranial radiotherapy (RT) and pyrotinib both demonstrate efficacy in HER2-positive breast cancer brain metastases (BCBM); however, the optimal sequencing of these modalities remains to be established. We evaluated survival across treatment sequences within a real-world cohort. This retrospective, two-centre study included 101 patients with HER2-positive BCBM treated with cranial RT plus pyrotinib (June 2018-July 2025). Based on treatment sequence, patients were categorized into: concurrent RT and pyrotinib (Group A, n = 41); RT after intracranial progression on pyrotinib (Group B, n = 38); and pyrotinib upon progression following RT (Group C, n = 22). The primary endpoint was CNS-PFS. Survival outcomes were assessed via Kaplan-Meier estimation and Cox proportional hazards models. At a median follow-up of 43.3 months, 63 patients (62.4%) had died and 70 (69.3%) experienced CNS-PFS events. Median CNS-PFS was 14.8 months (95% CI 10.68-19.92) overall, and 14.3, 15.0, and 21.4 months in groups A, B, and C, respectively ( P = 0.252); median OS was 36.0 months (95% CI 28.0-39.7) overall, and 33.0, 35.4, and 42.0 months in groups A, B, and C, respectively ( P = 0.281). Focal cranial RT was independently associated with longer OS (HR 0.56, 95% CI 0.34-0.94; P = 0.028). Any-grade adverse events occurred in 100 of 101 patients (99.0%); grade ≥ 3 events occurred in 2.4%, 7.9%, and 4.5% of groups A, B, and C, respectively (all P > 0.05), and radiation necrosis occurred in 7 patients (6.9%). An exploratory threshold of RT initiated >3.9 months before pyrotinib (OS 49.9 vs 29.8 months; HR 0.31, 95% CI 0.11-0.91; P = 0.025) did not withstand internal validation. Treatment sequence did not significantly affect OS or CNS-PFS. Focal cranial RT was independently associated with longer survival, and toxicity was manageable. The proposed timing threshold is hypothesis-generating and warrants prospective validation.

Ovarian cancer (OVCA) is one of the most common gynecological tumor and is the eighth most common cause of cancer death in women. Sex comb on midleg-like 1 (SCML1) plays an important role in the regulation of embryonic development, but its role in OVCA has not been detected. SCML1 was identified to be associated with cisplatin resistance in OVCA. The expression of SCML1 in OVCA tissues was verified by testing clinical samples. The effect of SCML1 on the proliferation and drug resistance of OVCA cells was investigated in vivo and in vitro . The expression of SCML1 is significantly lower in OVCA cisplatin-resistant tissues. After SCML1 knockdown, the proliferation ability and cisplatin resistance of OVCA cells were significantly enhanced. The overexpression of SCML1 can inhibit the expression of E2F transcription factor 1 (E2F1) and promote the expression of O-linked N-acetylglucosamine transferase (OGT).

Ovarian cancer is a major cause of gynecologic cancer mortality worldwide, with disproportionately poor outcomes in Latin America (LATAM). Variants in homologous recombination repair genes, especially BRCA1/2 , are predictive biomarkers for platinum-based chemotherapy and PARP inhibitors. However, data on the prevalence and spectrum of homologous recombination repair variants in LATAM populations remain limited. To synthesize the prevalence and spectrum of pathogenic and likely pathogenic variants in homologous recombination repair pathway genes among LATAM ovarian cancer patients and highlight clinical and research implications. The review protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered in the international prospective register of systematic reviews (PROSPERO; registration number CRD420251019706). We systematically searched MEDLINE, EMBASE, Scopus, Web of Science, LILACS, Cochrane, and Epistemonikos through April 2025. Eligible studies included LATAM ovarian cancer patients tested with multigene panels covering homologous recombination repair genes beyond BRCA1/2 . Data extraction followed 2025 ACMG/AMP guidelines, and study quality was assessed with the Joanna Briggs Institute checklist. Pooled prevalence was estimated using random- and common-effects meta-analysis. Eight studies published between 2017 and 2023, including 442 patients with ovarian cancer from Brazil, Argentina, Mexico, Chile, and Colombia, were included in the systematic review. Following variant curation and reclassification, 7 studies comprising 433 patients and 96 pathogenic/likely pathogenic homologous recombination repair variant carriers were retained for prevalence analysis, yielding a crude prevalence of 22.2%. Pathogenic variants predominated (91.7%), with BRCA1 (55.2%) and BRCA2 (40.6%) accounting for ∼96% of carriers. Non- BRCA homologous recombination repair variants ( CHEK2, BARD1, and RAD51D ) accounted for 4.2%. The pooled prevalence of germline pathogenic/likely pathogenic homologous recombination repair variants was 17% (95% CI, 9%-26%; I²=56.2%), increasing to 20% (95% CI, 16%-23%; I²=0%) after sensitivity analysis excluding 2 micro-cohorts. Five recurrent variants were identified across multiple cohorts and countries. No study evaluated somatic homologous recombination repair variants or homologous recombination deficiency assays. This first systematic synthesis of homologous recombination repair variants in LATAM ovarian cancer reveals a predominance of BRCA1/2 but also underscores the relevance of non- BRCA homologous recombination repair genes. Lack of somatic testing, methodological heterogeneity, and limited regional coverage highlight the need for standardized approaches, multicenter collaboration, and equitable access to genomic diagnostics in the region. This systematic review highlights both opportunities and barriers for implementing homologous recombination repair testing in ovarian cancer across Latin America. While BRCA1/2 remains the predominant genes, non- BRCA variants are also clinically relevant. Importantly, we identified substantial inequities in the distribution of genomic testing capacity, with most data concentrated in Brazil and Argentina, leaving many countries unrepresented. The absence of somatic homologous recombination repair/homologous recombination deficiency testing and heterogeneous sequencing approaches further limit regional comparability and access to precision therapies. Addressing these disparities through standardized testing strategies and collaborative networks is critical to ensure equitable access to genetic counseling and targeted treatments.

Adjuvant breast cancer (BC) radiotherapy (RT) improves survival and local control, but cardiovascular (CV) toxicity remains a concern. This retrospective study investigated the association between RT doses to cardiac substructures and CV toxicity 15 years after BC RT. Women with unilateral BC diagnosed between 2007 and 2008, treated with RT at [Anonymous] were retrospectively included. Patients with major adverse cardiac events (MACE) were matched to controls by CV risk factors, anthracycline and anti-HER2 therapy. Cardiac substructures were delineated on simulation scans, and multivariable logistic regression was performed to assess associations between RT doses to these substructures and MACE or other CV events. After a median follow-up of 16.5 years (IQR 16.1-17.1), and inclusion of 878 patients, 173 patients experienced MACE and were matched to 167 controls. All patients underwent adjuvant RT using 3-dimensional conformal RT to a total dose of 50 Gy in 25 fractions, with or without a boost to the tumor bed. New individual cardiac toxicities included: atrial fibrillation (AF) 98/878 (11.16%), heart failure (HF) 82/878 (9.34%), coronary artery disease (CAD) 46/878 (5.24%) and valvular disease 180/878 (20.50%). Mean heart doses were 6.62 ± 5.20Gy (MACE) and 5.76 ± 4.96Gy (controls) ( p = 0.0916). Compared with controls, patients with MACE had significantly higher disease stage and more frequent histories of CAD, AF and HF. Maximum RT doses to the left atrium (LA) were associated with MACE, new-onset HF, AF and valvular disease, while mean RT dose to the left ventricle (LV) was associated with development of CAD (all p < 0.05). This study demonstrates that patients treated with RT for BC may experience diverse CV toxicities during long-term follow-up. Higher doses to left-sided cardiac substructures, particularly the LA and LV, were associated with specific CV endpoints, while MHD was not associated with toxicity.

The human epidermal growth factor receptor 2 (HER2) plays an important role as a transmembrane receptor, contributing to signaling activities implicated in cellular proliferation, differentiation, and survival. Across select tumor types, HER2 is pro-oncogenic, facilitating cancer initiation, progression and metastatic spread, leading towards treatment resistance. Further, cell surface presentation and signaling activity of HER2 has led to the development of precision oncology therapeutic approaches. In this study, a HER2-targeting DNA aptamer was modified into a novel chimeric sequence with an RNA sense strand that was hybridized with a complementary antisense RNA or DNA sequence for aptamer-mediated HER2 cellular uptake in a representative HER2 positive (+) SKBR3 breast cancer cell line. The incorporation of antisense oligonucleotide (ASO) and short interfering (si) RNA within the chimeric HER2-aptamer elicited favorable hybrid duplex secondary structures and thermal stability profiles for biological activity. Enzymatic (Ribonuclease H, RNase H) digestion of the RNA sense strand made the chimeric HER2-aptamer:ASO hybrid applicable for antisense and with siRNA for RNA interference (RNAi) gene silencing activities against the stress-inducible oncoprotein, Glucose Regulated Protein 78, GRP78, as a key regulator of cancer cell survival and apoptosis. The chimeric ASO and siRNA conjugated aptamer demonstrated cellular binding and uptake activities directly in the HER2 presenting SKBR3 cell line and downstream GRP78 silencing (siRNA) activity that was dependent on a Lipofectamine-based formulation, underscoring the importance of the transfection agent for cellular delivery of genetic therapies.

In breast ultrasound segmentation, there is a strong demand for lightweight yet high-quality models for practical deployment. Knowledge distillation (KD) is a natural solution for transferring knowledge from high-capacity models to compact ones. However, the teacher's training domain is often inaccessible in clinical practice, leading to a source-domain-unknown KD setting. Under this condition, domain discrepancies between teacher and student distributions can significantly reduce distillation effectiveness. From a theoretical perspective, we analyze KD under domain discrepancies and show that, while KD can still be beneficial, its gains diminish when the support overlap between the teacher and target distributions is small. Our analysis further suggests that enlarging the support of the target distribution can increase this overlap and thereby strengthen knowledge transfer. Motivated by this insight, we propose a Data Diffusion-Enhanced Knowledge Distillation paradigm (D 3 -KD) that augments target-domain data to facilitate knowledge transfer under unknown source domains. Specifically, leveraging the generative capability of diffusion models, we design a Drift-Corrected Efficient Diffusion (DCED) module to effectively expand the target data distribution while correcting undesired drift and improving sampling efficiency via shifted initialization. Extensive experiments on breast ultrasound segmentation demonstrate that D 3 -KD consistently improves distillation performance in source-domain-unknown scenarios.

Aromatase inhibitors (AIs) suppress estrogen biosynthesis by blocking the conversion of androgens to estrogens. Although they are established endocrine therapies in postmenopausal breast cancer, their mechanism has led to off-label and non-medical use in men, including performance-enhancing drug practices, post-cycle therapy, supplement-related contexts, and attempts to manipulate the testosterone-estradiol balance. This review summarizes the pharmacology of clinically approved and non-approved aromatase-inhibiting compounds and evaluates their endocrine and health-related consequences in male populations. Across clinical and experimental studies, aromatase inhibition generally reduced estradiol and increased gonadotropins and testosterone. Responses were heterogeneous and influenced by baseline endocrine status, clinical context, treatment protocol, and analytical methodology. Group-level summaries may obscure substantial interindividual variability. Most studies did not systematically evaluate men with prior anabolic-androgenic steroid exposure, despite the relevance of this subgroup to performance-enhancing drug use and post-cycle endocrine recovery. AI-induced testosterone increases appeared to develop rapidly, reach an apparent ceiling, and generally reverse after discontinuation. However, biochemical increases in testosterone did not consistently translate into improved sexual function, physical performance, or broader patient-reported benefit. In adolescent boys, aromatase inhibition may delay skeletal maturation, but the long-term endocrine, skeletal, and developmental consequences of estrogen deprivation remain incompletely defined. The available evidence supports a cautious, indication-specific view of AI use in men. AIs should not be regarded as general testosterone-restoring or performance-enhancing agents. Better phenotyping and mass-spectrometric steroid profiling are needed to clarify clinically relevant subgroups and health risks.

MicroRNAs (miRNAs) precisely coordinate complex gene regulatory networks and serve as critical biomarkers for disease diagnosis. However, simultaneous monitoring of intracellular multiple miRNAs remains constrained by inefficient delivery and insufficient signal gain. Herein, we construct a self-reinforced DNAzyme nanomachine (Dz@hMNS) by integrating a honeycomb MnO 2 nanosponge (hMNS) with a miRNA-responsive DNAzyme system for simultaneous visualization of miR-21, miR-155, and miR-10b in living cells. Upon encountering the glutathione (GSH)-rich intracellular environment, the hMNS scaffold efficiently delivers miRNA-responsive DNAzyme system into cells and releases Mn 2+ as an essential cofactor, facilitating target miRNAs-activated cyclic cleavage of reporter probes to generate amplified fluorescence signals. This self-reinforced mechanism operates without either protein enzymes or exogenous amplification, achieving a detection limit of 50.13 fM for miR-21, 34.78 fM for miR-155, and 49.10 fM for miR-10b. By simultaneously profiling three miRNAs, this Dz@hMNS nanomachine can discriminate breast cancer patients from healthy donors and distinguish among stages I-III breast cancers with 100% accuracy (AUC = 1.000), superior to single-miRNA analysis. Moreover, it enables real-time imaging of multiple miRNAs in living cells with minimal crosstalk and can be reprogrammed to detect other RNA species (e.g., piRNAs, lncRNAs, and circRNAs), with promising applications in biological research and cancer diagnosis.

Four unprecedented alkaloids, melomortsines A-D (1-4), and 13 known alkaloids were isolated from Melodinus morsei Tsiang. Melomortsine A, a monoterpenoid quinolone alkaloid, had an unprecedented 6/6/5/5/5 pentacyclic quinolone alkaloid skeleton. Detailed nuclear magnetic resonance spectra analysis, electronic circular dichroism calculations, and X-ray crystallographic analysis were used to elucidate their structures. These compounds could inhibit the pro-inflammatory cytokine and chemokines secretion, and compound 1 exhibited the strongest inhibitory effect. Scandine N 4 -oxide (5) significantly inhibited 4T1-BrM by reducing both polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs) to remodel immune microenvironment in the brain. Mechanistically, scandine N 4 -oxide inhibited the secretion of chemokines by regulating JAK2/STAT3 signaling pathway of M2 type microglial cells, thereby suppressing the recruitment of MDSCs. Overall, scandine N 4 -oxide can effectively inhibit the process of BrM in breast cancer, providing a new potential strategy for the therapeutic of breast cancer BrM.

Breast cancer (BC) is the most common malignant tumor among women worldwide, and its chemotherapy resistance poses a major challenge in clinical treatment. Triple-negative breast cancer (TNBC) is a specific type of breast cancer that has attracted significant attention due to its extremely poor prognosis. The effectiveness of treatment and the prognosis for survival are significantly impacted by paclitaxel (PTX) resistance, a key chemotherapy medication for BC patients, particularly those with TNBC. CD24 is considerably overexpressed in PTX-resistant MDA-MB-231 cells and tissues, and it is directly linked to a bad prognosis for patients, according to this study's bioinformatics analysis and experimental confirmation. According to mechanistic research, CD24 suppresses MDA-MB-231 cell apoptosis while increasing invasion and proliferation by directly interacting with Endothelin-1 (EDN1) to activate the NFκB signaling pathway. Experiments both in vitro and in vivo demonstrate that CD24 knockdown dramatically reduces tumor development and increases PTX sensitivity. The CD24-EDN1-NFκB axis has a crucial role in PTX resistance in TNBC, according to this study, offering a new therapeutic target for treating chemotherapy resistance.

Thyroid hormones (TH) influence tumor biology through both genomic and non-genomic mechanisms. Specifically, thyroxine (T4) activates signaling pathways linked to cancer progression through interactions with nuclear receptors, such as TRβ1, and membrane receptors, including integrin αvβ3. Nevertheless, the precise role of T4 in breast cancer cell behavior and its underlying molecular mechanisms remain incompletely understood. The effects of physiological concentrations of T4 (10 -9 M) on proliferation, cell viability, apoptotic signaling, and activation of intracellular pathways were evaluated in human mammary cell lines. Tumor cell lines (MCF-7 and MDA-MB-231) and the non-tumor mammary epithelial cell line MCF-10A were treated with T4 alone or in combination with the thyroid hormone receptor antagonist 1-850. Cell proliferation was measured using the MTT assay, and viability was determined by trypan blue exclusion. Protein expression and signaling pathways were analyzed by Western blot, including assessment of apoptotic markers (caspases, PARP, Bax, Bcl-2), PCNA, steroid hormone receptors, and signaling mediators such as PI3K, AKT, and ERK. Immunocytochemistry was used to evaluate TRβ1, integrin αvβ3, and Ki67 expression. T4 treatment increased proliferation and survival in hormone-sensitive tumor cells, accompanied by modulation of apoptosis-related proteins and activation of the PI3K/AKT pathway. The antagonist 1-850 selectively attenuated TRβ1-dependent effects, enabling distinction between genomic and integrin-mediated mechanisms. These effects were observed exclusively in hormone-sensitive tumor cells. These findings support a role for T4 in breast cancer progression and identify TH-related signaling pathways as potential therapeutic targets.

Ovarian cancer represents one of the most lethal gynecological malignancies, marked by a high recurrence rate and dismal prognosis. Existing targeted treatments face challenges such as limited applicability, modest effectiveness, and considerable costs, underscoring the demand for novel therapeutic alternatives. Growing research suggests that triggering a significant intracellular reactive oxygen species (ROS) surge can selectively induce oxidative destruction and death in tumor cells with compromised redox balance, while largely sparing normal cells. In this work, we designed lanthanum-doped zinc sulfide (ZnS:La) nanocrystals as an efficient sonocatalyst to augment sonodynamic treatment for ovarian cancer. Under ultrasound exposure, ZnS:La demonstrated improved charge separation and a notable boost in ROS generation, leading to substantial oxidative injury in cancer cells. Concurrently, the slow release of La 3+ ions contributed to lysosomal membrane disruption, increasing cellular susceptibility to oxidative stress. These processes promoted the formation of PANoptosomes and initiated PANoptosis-a synergistic type of programmed cell death encompassing apoptosis, pyroptosis, and necroptosis. In evaluations using patient-derived organoids, subcutaneous grafts, and orthotopic ovarian tumor models, ultrasound-activated ZnS:La consistently inhibited tumor progression and spread. This study introduces a powerful sonocatalyst-based approach to engage multiple programmed cell death mechanisms, highlighting a potential new direction for ovarian cancer therapy.

Ovarian cancer remains the most lethal gynecological malignancy, primarily because of the absence of reliable early detection methods. Microfluidic biosensors have emerged as promising platforms for rapid, sensitive, and minimally invasive detection of ovarian cancer biomarkers. This review provides a comprehensive analysis of recent advances in microfluidic biosensing technologies for early ovarian cancer detection. We systematically examine various detection modalities, including electrochemical, optical, and mass-based sensors, with an emphasis on their integration with microfluidic platforms for point-of-care applications. Key biomarkers, including CA125, HE4, circulating tumor cells, exosomes, and circulating tumor DNA, are discussed in the context of multiplexed detection strategies. The review highlights critical performance metrics such as sensitivity, specificity, limit of detection, and clinical validation status. Furthermore, we address current challenges, including sample preparation, standardization, and clinical translation barriers. Our analysis revealed that integrated microfluidic platforms combining multiple biomarker detection methods with advanced nanomaterials and machine learning algorithms demonstrated the greatest promise for transforming ovarian cancer screening. Future directions toward clinical implementation require standardized validation protocols, large-scale prospective studies, and regulatory pathway clarification to realize the full potential of these innovative diagnostic technologies.

Epithelial ovarian carcinoma (EOC) comprises five main histological subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell (CCOC), mucinous (MOC), and endometrioid (ENOC). Each histotype harbors specific genomic alterations and clinical outcome. Few studies systematically compared the tumor immune microenvironment across the five subtypes. We performed 7-plex (CD45, CD8, CD68, CD163, FoxP3, CD20, and cytokeratin) sequential immunohistochemistry on a clinically annotated tissue microarray including 139 EOC representing the five subtypes and 26 borderline tumors (serous and mucinous). Digital pathology was used to quantify immune cell abundance, their spatial distribution (stroma vs tumor core), and correlation with survival. Immune cells were dominated by macrophages and more abundant in the stroma than tumor core across the five subtypes, consistent with immune excluded pattern. Compared to HGSOC, CCOC displayed the highest infiltration by CD45 + leukocytes and CD68 + macrophages, particularly M2-like CD163 + cells, suggesting a macrophage-rich, immunosuppressive phenotype. LGSOC exhibited the highest infiltration by intraepithelial FoxP3 + regulatory T cells. Comparison of borderline tumors with invasive carcinoma (LGOSC and MOC) revealed that malignant progression is accompanied by loss of CD8 + T cells, enrichment in regulatory T cells and increase of CD163 + /CD68 + ratio, consistent with immune evasion during tumorigenesis. There was a trend toward better survival in HGSOC highly infiltrated by lymphocytes, either intraepithelial (CD8 + and FoxP3 + ) or stromal (FoxP3 + and CD20 + ). EOC is characterized by histotype-specific immune milieux defined by macrophage dominance, epithelial immune exclusion and dynamic immune remodeling during progression from borderline tumors to invasive carcinomas.

Epithelial ovarian cancer (EOC) is a heterogenous disease with frequent late-stage diagnosis and high mortality rates, for which no reliable screening tests exist. In recent years, epigenetic biomarkers in the form of DNA methylation in CpG-rich regions have gained increased attention in the scientific community due to their robust nature and accessibility, allowing for diagnosis without the need for invasive surgery. In this study, we investigated the aberrant methylation of promoter regions in early stage EOC through non-parametric methods, with the purpose of characterizing candidate epigenetic biomarkers. The approach was used on a cohort of early stage EOC samples, and results were compared to existing programs for differential methylation. Significant regions were then used to construct a CpG panel for stratifying EOC histotypes through predictive classification in external data. Identified promoter regions were highly reproducible across cohorts, and the constructed CpG model stratified histotypes in external cohorts through predictive classification. Comparisons against other DMP and DMR callers showed a degree of homogeneity between results but also revealed promoter regions that were overlooked despite clear signs of aberrant methylation. Finally, EOC histotypes were found to differ in their methylation distribution types, and results indicate that methods sensitive to non-normally distributed data may be poorly suited to compare groups with different distribution types. The non-parametric approach identified aberrantly methylated promoter regions that were highly reproducible across cohorts. Results from predictive classification indicate that these regions may be useful for the purpose of EOC histotype stratification.

Immune checkpoint regulators, such as the V-domain Ig suppressor of T cell activation (VISTA), play a critical role in shaping the tumor microenvironment (TME) and facilitating immune evasion. In ovarian cancer, VISTA exhibits more abundant and consistent expression than other immune checkpoints, including Programmed Death-Ligand 1 (PD-L1). This study examined the role of platelets in the regulation of VISTA in ovarian cancer using both in vitro and in vivo models. Our findings demonstrate that platelets upregulate VISTA expression in both myeloid and tumor cells, thereby promoting an immunosuppressive TME. Elevated VISTA levels were associated with higher platelet counts and poorer clinical outcomes. These results highlight that platelet-mediated VISTA upregulation is a potential therapeutic target for improving antitumor immune responses in ovarian cancer. What is the context? Ovarian cancer is a leading cause of death from gynecologic cancers. The tumor microenvironment (TME) in ovarian cancer is strongly immunosuppressive, limiting the success of current immunotherapies. Platelets, known for their role in blood clotting, are increasingly recognized as contributors to cancer growth and immune evasion. They can interact with tumor and immune cells, releasing molecules that suppress immune responses. VISTA, a newer immune checkpoint molecule, is widely expressed in ovarian cancer and may act as a key regulator of tumor-induced immune suppression. What is new? This study reveals that platelets increase the expression of VISTA in both ovarian cancer cells and immune cells, such as monocytes. In mouse models, high platelet counts led to increased VISTA expression and faster tumor growth, while platelet depletion reduced both. Human ovarian cancer samples from patients with elevated platelet counts also showed higher VISTA levels. Blocking PD-L1, another immune checkpoint, led to increased VISTA expression, suggesting that tumors may use VISTA to bypass PD-L1–directed therapies. What is the impact? These findings identify a new mechanism by which platelets promote immune suppression in ovarian cancer. VISTA may help tumors evade immune attack, particularly in patients with high platelet counts. Targeting both platelet activity and VISTA could enhance the effectiveness of immunotherapies and improve outcomes for patients with ovarian cancer.

As one of the most lethal gynecological malignancies, ovarian cancer (OC) significantly impacts the health and quality of life of women globally. Currently, surgical intervention and chemotherapy remain the primary clinical treatment modalities for OC. With ongoing advancements in the understanding of molecular mechanisms, various therapeutic strategies such as poly-ADP-ribose polymerase inhibitors (PARPi) treatment, immunotherapy, and combination therapies have also been introduced into clinical practice. However, significant challenges, such as systemic adverse effects, high recurrence rates, and the development of drug resistance, greatly limit their efficacy. To overcome these limitations, nanotherapeutics have emerged as promising multifunctional drug delivery systems for both the diagnosis and treatment of OC over the past few decades, owing to their ability to specifically target malignant tissues and enable controlled drug release. In this paper, we first review the tumor-targeting mechanisms of nanoparticles, which can guide researchers in designing suitable and effective nanomedicines with translational potential. We subsequently provide a detailed overview of several representative nanotherapeutic approaches used in the treatment of OC, including their roles in enhancing chemotherapy, PARPi therapy, immunotherapy, light- or ultrasound-mediated therapies, and various combination strategies. Finally, we discuss future perspectives and potential directions for nanotherapeutics in advancing personalized and targeted treatment of OC.

Cisplatin resistance remains a major challenge in ovarian cancer, limiting treatment efficacy and reducing patient survival. While FOXM1 and calcium (Ca 2+ signaling have been individually implicated in chemoresistance, how transcriptional regulation is linked to Ca 2+ -dependent survival signaling remains poorly understood. To address this gap, we integrated bioinformatic analyses with functional and mechanistic studies in cisplatin-resistant (CR) ovarian cancer models. We found that FOXM1 transcriptionally activate STIM1, thereby enhancing store-operated Ca 2+ entry (SOCE) and sustaining cytosolic Ca 2+ levels. Elevated Ca 2+ influx-activated downstream interferon (IFN)/STAT1 signaling and increased expression of IFN-stimulated genes associated with DNA repair and anti-apoptotic programs. FOXM1 or STIM1 depletion and pharmacological SOCE inhibition attenuated STAT1 activation and restored cisplatin sensitivity, whereas STIM1 re-expression rescued the resistance phenotype following FOXM1 depletion. Using A2780/ACR and IGROV1/ICR ovarian cancer models, together with analyses of TCGA-OV and multiple GEO cohorts, we demonstrate that FOXM1 transcriptionally activates STIM1, thereby enhancing store-operated Ca 2+ entry and promoting STAT1-dependent IFN signaling. Genetic or pharmacological disruption of this pathway restored cisplatin sensitivity, identifying the FOXM1-STIM1/SOCE-STAT1 axis as a potential therapeutic vulnerability in platinum-resistant ovarian cancer. This study provides mechanistic insight into chemoresistance and highlights avenues for therapeutic intervention in patients with high FOXM1/STIM1 expression.

Ovarian cancer (OC) exhibits the highest mortality rate among gynecological cancers, and the development of chemotherapy resistance serves as the primary cause of patient recurrence and death. Natural products hold promise in reversing cisplatin (DDP) resistance. Trigonelline is a natural alkaloid possessing anti-tumor activity; however, it remains uncertain whether it can reverse DDP resistance in OC. In this study, DDP-resistant OC cell lines SKOV-3/DDP and A2780/DDP were successfully established. Cells were treated with non-toxic concentration of trigonelline in combination with DDP, and the molecular mechanism was investigated through the overexpression of Nrf2. Cell viability was detected to assess the sensitivity of the cells to DDP. Mitochondrial damage was evaluated by observing mitochondrial morphology, measuring mitochondrial membrane potential, ATP production, and ROS. Ferroptosis was assessed by detecting the levels of lipid peroxidation, MDA, SOD, Fe 2+ , and GSH/GSSG ratio in the cells. Additionally, the expression levels of ferroptosis-related proteins, namely Nrf2, HO-1, GPX4, and SLC7A11, were also detected. The results indicated that the utilization of low-concentration trigonelline exerted no toxic influence on OC drug-resistant cells, and instead potentiated the cytotoxicity of DDP against these cells. Furthermore, in comparison with the treatment using DDP alone, the combined treatment of trigonelline and DDP induced more severe mitochondrial damage and ferroptosis in drug-resistant cells. This led to the accumulation of ROS, notable increases in lipid peroxidation, MDA, and Fe 2+ levels within the cells, while decreasing SOD activity and the ratio of GSH/GSSG, and down-regulating the expression of Nrf2, HO-1, GPX4, and SLC7A11 proteins. Nevertheless, the overexpression of Nrf2 reversed the combined effect of trigonelline and DDP. These results indicate that trigonelline reverses DDP resistance in OC cells by promoting ferroptosis via the regulation of the Nrf2/GPX4 signaling pathway.

The ERK/MNK/eIF4E signaling axis is critically involved in cap-dependent translation and significantly impacts survival and chemotherapy resistance in ovarian cancer. Clinical data indicate that elevated eIF4E expression is an independent prognostic marker for poor overall survival (HR = 1.17, p = 0.027). However, there has yet to be a systematic evaluation of FDA-approved agents for their efficacy as MNK/eIF4E inhibitors. In the present study, a total of 2180 FDA-approved compounds were screened using a comprehensive approach integrating machine learning, molecular docking, molecular dynamics, and binding free energy analysis to identify potential MNK1 modulators. Ibrutinib and Entrectinib emerged as the most promising candidates, forming stable complexes with MNK1 and displaying favorable binding energies (Entrectinib: ΔG = -131.66 ± 2.05 kJ/mol; Ibrutinib: ΔG = -87.36 ± 2.04 kJ/mol). Notably, Ibrutinib, conventionally recognized as a BTK inhibitor, and Entrectinib, a tropomyosin receptor kinase inhibitor, exhibited previously unreported off-target interactions with MNK1/eIF4E, suggesting new therapeutic applications for both agents. In vitro validation was conducted using the A2780-s and A2780-cp cell lines, with A2780-cp selected for its elevated MNK/eIF4E activity. Niclosamide, identified as an MNK/eIF4E inhibitor, served as a positive control in this investigation. Both compounds significantly diminished cell viability, lowered the p-eIF4E/eIF4E ratio as determined via Western blot analysis, impaired clonogenic survival. This study represents the first examination of the roles of Entrectinib and Ibrutinib as modulators of MNK1/eIF4E in ovarian cancer, providing substantial functional evidence for their efficacy in modulating the MNK/eIF4E pathway with eIF4E Phosphorylation-Suppressing Activity.

Aurora A kinase overexpression has been implicated in ovarian cancer progression, highlighting its potential as a therapeutic target. In this study, we performed structure-based virtual screening of our proprietary natural product database, identifying hinokiflavone (HNK) as a novel Aurora A inhibitor. Kinase profiling assays revealed that HNK exhibits multi-target inhibitory activity, with preferential potency against Aurora A and B. We developed the first efficient total synthesis of HNK derivatives featuring a key Chan-Lam coupling reaction. Based on the different positions of methoxy and hydroxyl groups in the structure of HNK and its derivatives, we also compared their molecular docking simulation and molecular dynamics simulation, and found that as the number of hydroxyl groups increased, the activity of inhibiting Aurora A gradually increased. The retention of hydroxyl groups at specific positions plays a crucial role in the activity of HNK. The aforementioned research provides a preliminary theoretical foundation for a subsequent structural modification.