Original research publications

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder whose terminology inadequately reflects its systemic nature. The proposed renaming to polyendocrine metabolic ovary syndrome (PMOS) aims to better represent its pathophysiology. To present the European Society of Gynaecology (ESG) position regarding the proposed terminology change and its implementation. Expert consensus and narrative synthesis of current scientific evidence and international recommendations. ESG supports a structured, patient-centered transition strategy. Recommendations include prioritizing patient communication, implementing a gradual transition with prolonged dual terminology use, and integrating the new terminology systematically into scientific and educational frameworks. The importance of interdisciplinary clarity and the central role of gynecological endocrinology are emphasized. A phased and clearly communicated transition will enhance conceptual accuracy while preserving patient understanding, continuity of care, and clinical coordination. PCOS terminology inadequately reflects its endocrine–metabolic nature.ESG supports transition to PMOS through a phased, patient-centered approach.Dual terminology (‘PMOS, formerly known as PCOS’) should be maintained long-term.Systematic integration into guidelines and education is recommended.Gynecological endocrinology remains central in patient management.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. While diagnostic criteria have historically varied, the Rotterdam criteria, established in 2003, are now the standard. This classification identifies four PCOS phenotypes based on the presence and/or absence of three key features: ovulatory dysfunction (OD), hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). Despite phenotypic differences, current clinical guidelines treat PCOS as a homogeneous condition when assessing pregnancy risks. Therefore, this narrative review examines variations in gestational outcomes across PCOS phenotypes in both natural and assisted reproductive technology (ART)-conceived pregnancies. A search of three databases (PubMed, Cochrane, and Google Scholar) using key terms identified 13 eligible retrospective and prospective studies reporting gestational outcomes in PCOS phenotypes. Findings indicate that phenotypes characterized by HA (A, B, and C) are at higher risk for preeclampsia, gestational diabetes, and miscarriage in natural pregnancies. However, in ART-conceived pregnancies, Phenotypes A and D exhibited higher risks of adverse outcomes, while Phenotypes A and C showed significantly lower live birth and cumulative live birth rates. These results reveal inconsistencies in pregnancy risks across phenotypes and conception methods, suggesting differences in the underlying mechanisms. The findings challenge the one-size-fits-all approach to pregnancy counseling in PCOS. Incorporating phenotype-specific risk stratification into clinical guidelines could enhance maternal and neonatal outcomes, particularly for high-risk phenotypes. Further research is needed to refine pregnancy care strategies tailored to individual PCOS phenotypes.

To compare depression prevalence using the Hospital Anxiety and Depression Scale focused on depression (HADS-D), the Patient Health Questionnaire-9 (PHQ-9) and the Patient Health Questionnaire-2 (PHQ-2). It also evaluated the psychometric properties of these instruments and their agreement at different cutoff scores. A cross-sectional study with 119 women with PCOS. Participants completed all three measurements to assess depression. The study compared depression prevalence and analysed psychometric properties using Cohen's Kappa ( κ ), coefficient ( ρ ), Spearman's correlation and Cronbach's alpha ( α ). Depression rate among PCOS women varied significantly by screening tool: 2.52%-26.89%. However, there was poor agreement and correlation between HADS-D and PHQ-9. In contrast, using cutoff scores of HADS-D ≥ 7 and PHQ-9 ≥ 10 yielded strong agreement ( κ = 0.731) and correlation ( ρ = 0.731). The PHQ-2 ≥ 3 had reasonable correlations with HADS-D ≥ 7 ( κ = 0.596, ρ = 0.599) and PHQ-9 ≥ 10 ( κ = 0.596, ρ = 0.599). Depression rates in PCOS women vary by evaluation technique. This study recommends a cutoff score of ≥7 for the HADS-D and ≥10 for the PHQ-9 to enhance screening accuracy among Thai PCOS women. The PHQ-2 also represents a convenient alternative tool due to its brevity and user-friendliness. We propose that the PHQ-9, with a score of ≥10, constitutes the most suitable screening instrument for Thai women with PCOS.

This retrospective study compares pregnancy outcomes in polycystic ovary syndrome (PCOS) patients across different controlled ovarian stimulation (COS) protocols-specifically GnRH antagonist and GnRH agonist cycles-combined with various frozen embryo transfer(FET) preparation methods, such as hormone replacement therapy (HRT) and ovulatory cycles. Despite the known variations in COS and FET protocols, the optimal combination for improving pregnancy outcomes in this population remains unclear. We analyzed the first FET cycles of 2510 patients with PCOS at our center between January 2017 and September 2024. Baseline characteristics and pregnancy outcomes were compared using the Kruskal‒Wallis test, the chi-square (χ²) statistic, the Bonferroni correction for multiple comparisons, and inverse probability of treatment weighting (IPTW) adjustment. After IPTW adjustment, no significant differences were observed in live birth rates or other key reproductive outcomes among the four protocol combinations (all P > 0.05). Exploratory analyses revealed nonsignificant trends, suggesting two patterns: 1) GnRH agonist (vs. antagonist) COS protocols were associated with lower point estimates for the risks of preterm PROM and HDP; 2) ovulation (vs. HRT) cycles for FET preparation were similarly associated with lower point estimates for these risks. For PCOS patients, live birth success is equivalent regardless of COS/FET protocol combination, supporting flexible treatment personalization. Clinical decision-making involves a critical trade-off: GnRH agonist protocols and ovulation FET cycles may be associated with a trend toward lower obstetric morbidity, potentially linked to the promotion of a more physiological ovulatory milieu. This balance between immediate iatrogenic risk and long-term pregnancy health warrants further study.

Although assisted reproductive technology (ART) may increase the incidence of ectopic pregnancy (EP), the risk of EP and its associated risk factors in polycystic ovary syndrome (PCOS) patients, one of the target populations for ART, remain poorly understood. This retrospective study analyzed 377 PCOS patients undergoing IVF/ICSI (2010-2017). Standard ART protocols were applied, including controlled ovarian stimulation, oocyte retrieval, and embryo transfer. LASSO regression with 10-fold cross-validation selected 13 predictive features from 26 variables. Univariate and multivariate logistic regression analyses were performed for the overall cohort. A predictive nomogram was developed and internally validated using bootstrap resampling. Among 377 PCOS patients analyzed, LASSO regression identified 13 potential predictors including age, IVF cycles, and endometrial thickness (EMT). In women <35 years ( n = 333), multivariate analysis revealed three independent EP predictors: increased IVF cycle number (aOR = 4.592, 95%CI 1.48-14.21, p = 0.008), thinner EMT (aOR = 0.587, 95%CI 0.40-0.86, p = 0.007), and frozen embryo transfer (aOR = 0.044, 95%CI 0.01-0.22, p < 0.001). The developed nomogram incorporating these factors showed good discrimination (AUC 0.82) and calibration. Notably, clinical factors like abortion history and prolactin levels, while significant in univariate analysis, lost predictive value after multivariate adjustment in younger women. This study identifies three key predictors of ectopic pregnancy in younger PCOS (<35 year) patients undergoing ART: IVF cycle number, endometrial thickness, and frozen embryo transfer. The developed nomogram provides a validated assessment tool, particularly for younger patients. These findings highlight the need for personalized risk stratification and further research into underlying mechanism.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS are at an increased risk for adverse pregnancy outcomes, such as miscarriage and preterm birth. Endometrial receptivity plays a pivotal role in embryo implantation. However, there has been limited review or discussion regarding potential alterations in endometrial receptivity in PCOS patients, the nature of these changes, and their underlying mechanisms. In this review, we aim to summarize the alterations in endometrial receptivity associated with PCOS, highlight the impact of PCOS on endometrial receptivity, and explore the underlying mechanisms. Abnormal expression of key receptivity markers has been observed in both PCOS patients and animal models, which may contribute to reduced endometrial receptivity. The factors leading to impaired endometrial receptivity in PCOS are multifaceted, including hormonal imbalances, metabolic disturbances, chronic inflammation, and microbiota alterations. However, the intricate mechanisms behind PCOS-related endometrial dysfunction remain poorly understood. Further research is essential to unveil these complex mechanisms and improve fertility outcomes for women with PCOS.

Anovulation is a common and heterogenous cause of infertility with significant implications for metabolic health. Ovulatory disorders arise from disruption of the hypothalamic-pituitary-ovarian axis and are often characterized using the International Federation of Gynecology and Obstetrics hypothalamic dysfunction, pituitary dysfunction, ovarian dysfunction, and polyendocrine metabolic ovarian syndrome (PMOS) pathophysiologic framework. While many hypothalamic and pituitary causes of anovulatory infertility are treatable, primary ovarian insufficiency often requires assisted reproductive technology. In PMOS (formerly known as polycystic ovary syndrome), ovulation induction with an oral agent such as letrozole is considered first-line to reduce the risks of multiple gestation and ovarian hyperstimulation syndrome.

Polycystic ovary syndrome (PCOS) is a complex disorder resulting from the interaction of susceptibility genes with environmental factors. Current diagnostic criteria were established by expert consensus. Genome-wide association studies have shown that the phenotypes defined by these criteria share similar genetic architectures and do not reflect meaningful biological differences. Many complex disorders are defined by criteria designed to accommodate phenotypic diversity, yet such criteria often group the convergent expression of multiple genetic etiologies under a single clinical diagnosis. Data-driven mathematical methods, enabled by large phenotypic datasets, offer a strategy for partitioning this variation into groups corresponding to divergent genetic underpinnings.

Regularly updated global estimates are needed to monitor progress in cervical cancer screening, a key pillar of WHO's strategy to eliminate cervical cancer. We aimed to update estimates of cervical cancer screening coverage in 194 WHO member states and eight associated countries and territories for 2022, including the first global assessment of human papillomavirus (HPV) test-based screening adoption and roll-out. In this review and synthetic analysis, we used an established method to estimate standardised cervical cancer screening coverage in 2022. We used programme and population-based coverage data collected up to Jan 31, 2024, selecting the sources considered most representative of each country or territory's screening situation in 2022. Preliminary estimates were reviewed through a WHO country consultation (April-May, 2024; with additional responses received until July 2025). HPV testing coverage was estimated based on HPV test-based screening implementation levels, by country and year. Estimates were applied to 2022 populations and aggregated by region and country-income level. Cervical cancer screening recommendations were identified in 161 (80%) of 202 countries, with 92 (57%) of 161 countries recommending HPV test-based screening. By 2022, global coverage for women aged 30-49 years using any screening method (ie, cytology, HPV test, visual inspection with acetic acid, or combinations of these methods) was estimated at 19% (95% CI 15-22) for the previous year, 31% (26-35) in the previous 3 years, and 35% (30-39) in the previous 5 years; and 38% (33-43) of women had ever been screened. Disparities across regions and country-income levels were substantial: 5-year coverage was 26% (21-31) in low-income and middle-income countries, compared with 74% (64-84) in high-income countries. 5-year HPV test-based screening coverage was 8% (6-9) globally, 32% (25-40) in high-income countries, and 2% (2-3) in low-income and middle-income countries. In the past 5 years, 62 countries achieved more than 70% coverage with any screening method, and five countries with HPV testing. Despite policy updates, overall and HPV-specific screening coverage remains far below WHO's 70% target. Three in five women aged 30-49 years worldwide have never been screened, and 92% have never received HPV testing, with substantial disparities across regions and country-income levels. Scaling up high-performance HPV test-based screening, alongside HPV vaccination, will be essential to accelerate cervical cancer elimination. WHO, Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research, Government of Catalonia, and Horizon 2020.

Polycystic Ovary Syndrome (PCOS) imposes substantial metabolic and reproductive burdens. Exercise has emerged as a crucial lifestyle intervention, and corresponding scientific interest has expanded. This study provides a comprehensive bibliometric analysis of global research on the intersecting PCOS and exercise. Relevant publications (2005-2025) were collected from the Web of Science Core Collection (WoSCC). CiteSpace, VOSviewer, and bibliometrix were applied to map publication trends, international collaboration patterns, and evolving research hotspots. A total of 1,146 publications were identified, demonstrating sustained growth. The United States and Australia dominated productivity, collaborating primarily with India, the United Kingdom (UK), and Switzerland. Key research hotspots included metabolic syndrome, endothelial function, cardiovascular disease, and increasing emphasis on exercise-based interventions. Monash University and the University of Adelaide played central roles in institutional networks. Emerging themes, including oxidative stress and anxiety, have emerged in the broader PCOS literature and are closely linked to exercise-related biological pathways. Exercise is an increasingly prominent research focus in PCOS management. This analysis outlines the field's structural and thematic evolution and identifies opportunities for advancing scientific understanding. Strengthened international and multidisciplinary collaboration remains essential. PCOS is a common hormonal condition that impacts women’s health, leading to issues with fertility, metabolism, and overall quality of life. Exercise has become an important non-pharmacological intervention for managing PCOS, especially in women who are overweight. To gain a clearer understanding of global research on this topic, we analysed studies published from 2005 to 2025. We identified 1,146 papers, with the majority originating from the United States and Australia, and strong collaborations with countries such as India, the UK, and Switzerland. Prominent institutions included Monash University and the University of Adelaide. Research frequently focuses on how exercise impacts metabolism, cardiovascular health, and psychological well-being. More recently, emerging topics such as oxidative stress and anxiety have garnered increased attention. Our findings suggest exercise is increasingly acknowledged as a key therapeutic approach for PCOS, but stronger international collaboration is essential to advance both research and clinical care.

To identify patients who may benefit from an interstitial brachytherapy boost in the era of hypofractionation and widespread use of simultaneous integrated boost. Between 1984 and 2025, 112 articles were identified through a narrative search of the PubMed, MEDLINE, and Cochrane databases using the keywords "breast cancer", "boost", "interstitial brachytherapy", and "interventional radiotherapy". Two main areas were addressed: an update on risk factors and patient selection, and a review of boost techniques, with an emphasis on interstitial brachytherapy and comparisons with other techniques. Based on this evidence, we formulated recommendations on the role of brachytherapy boost in contemporary breast cancer (BC) treatment. Based on the available literature, the addition of a boost should be strongly recommended for patients aged <40 years, patients with positive margins, and patients aged <50 years with at least one of the following features: high-grade disease, extensive intraductal carcinoma, and/or a triple-negative phenotype. In other scenarios, including residual disease after neoadjuvant chemotherapy, a balanced shared decision should be made. Interstitial brachytherapy allows delivery of a high radiation dose to the target volume while significantly reducing the dose received by adjacent organs at risk. The use of brachytherapy as a boost has declined, particularly since the introduction of integrated and ultra-hypofractionated regimens. In the current era of breast cancer treatment, we suggest that brachytherapy remains a valuable option for selected high-risk patients because it enables dose escalation tailored to the risk volume while sparing surrounding organs at risk.

Cell cycle dysregulation is a hallmark of cancer; however, tumors retaining homologous recombination (HR)-proficiency remain a major challenge. Although PARP inhibitors effectively target HR-deficient cancers, targeted therapies for BRCA1 / 2 -wild-type, HR-proficient tumors are limited. High-grade serous ovarian cancer, approximately half of which is HR-proficient, illustrates that HR proficiency, together with replication stress and checkpoint dependence, may represent both a mechanism of therapeutic resistance and a druggable dependency on checkpoint-coupled DNA repair. This review synthesizes evidence that targeting either PLK1 or WEE1 independently exposes this vulnerability. PLK1 and WEE1 inhibition engage distinct mechanisms: PLK1 inhibition disrupts spindle assembly and HR competence, whereas WEE1 inhibition amplifies replication stress and forces premature mitotic entry. Nevertheless, both ultimately converge to compromise HR-associated repair, promote unresolved DNA damage, and trigger lethal mitotic catastrophe. Finally, we discuss biomarker-unselected trial failures, functional and replication stress-based patient stratification, and rational combinations with DNA-damaging agents and immunotherapy.

Bile acid derivatives have emerged as promising candidates in cancer therapeutics due to their ability to modulate key cellular signalling pathways, including those involved in apoptosis, cell cycle regulation, and inflammation. Structural modifications of natural bile acids have been shown to enhance their cytotoxicity against a variety of cancer cell types, including breast cancer. In this study we designed and synthesised a focused library of bile acid derivatives both via modification of the tetracyclic ring system to incorporate fluorine, and by structurally altering the bile acid nucleus. The anti-proliferative activities of nine synthesised derivatives, as well as bardoxolone methyl (CDDO-Me) which is a well-characterised IκB kinase (IKK) and NF-κB inhibitor and Nrf2 activator, were assessed in vitro against two clinically relevant breast cancer cell lines: MCF-7 (estrogen receptor-positive) and MDA-MB-231 (triple negative). Hence we report herein that two of the synthetic derivatives, specifically 3-deoxy-3α-fluoro-chenodeoxycholic acid (8, NZP208) and 12β-methyl-3,7-dioxo-17-epi-25-homo-18-nor-5β-cholan-25-oic acid (9, NZP302), have low micromolar IC 50 values against the selected cell lines, with IC 50 values for 8 being 6.44 ± 0.37 μM for MCF-7 and 7.16 ± 0.03 μM for MDA-MB-231, and for 9 being 5.53 ± 0.05 μM for MCF-7 and 7.24 ± 0.06 μM for MDA-MB-231. We further discuss structure-activity relationships for these compounds and show that they cause cell death in both cell lines via a statistically significant induction of apoptosis. In addition, in silico assessment predicted appropriate ADMET properties and compliance with Lipinski's rule of five.

In this real-world study, outcomes were evaluated in patients with stage III advanced epithelial ovarian cancer (EOC) with no visible residual disease (NVRD) after primary cytoreductive surgery (PCS), a subgroup excluded from the phase III PRIMA trial. The noninterventional, retrospective EUROPA study included patients with advanced (stage III or IV) EOC who initiated first-line maintenance (1LM) niraparib monotherapy (index date) between 1 October 2018 and 31 March 2023 in France, Germany, and Italy. Real-world time to treatment discontinuation (rwTTD) and real-world progression-free survival (rwPFS) were assessed among all patients and in a subgroup of patients with stage III disease and NVRD after PCS (stage III NVRD subgroup). Among 186 patients in this study, 48 were included in the stage III NVRD subgroup. Median (95% CI) rwTTD in the overall cohort versus stage III NVRD subgroup was 10.6 (7.8-18.6) versus 26.2 (8.9-not reached) months. In the overall cohort, median (95% CI) rwPFS was 14.7 (10.1-29.3) months but not reached in the stage III NVRD subgroup. rwTTD and rwPFS probabilities were higher for the stage III NVRD subgroup versus overall cohort at 12, 24, and 36 months after index date. In the real-world setting, patients with stage III advanced EOC and NVRD after PCS had descriptively better clinical outcomes than those in the overall cohort with advanced EOC. The use of 1LM niraparib in these patients, a subgroup excluded from the PRIMA trial, appeared to be associated with clinically meaningful real-world outcomes.

EGFR L858R is an activating mutation associated with aberrant EGFR signalling, and molecules capable of recognising this mutant remain of research interest. In this study, a virtual peptide library containing 59 319 heptapeptides was screened against the EGFR L858R crystal structure, leading to the identification of four peptides with favourable predicted binding ability. Among them, Peptide-1 showed the strongest binding affinity in MST assays ( K d = 0.35 ± 0.02 μM), with higher affinity than the reference peptide DTP-1. Integrated structural and dynamic analyses showed that Peptide-1 could form a relatively stable binding conformation with EGFR L858R. Peptide-1 reduced the viability of SKOV3, OVCAR3, and CaOV3 cells, showed weaker effects on IOSE-80 cells, and its activity was markedly attenuated after EGFR-targeting shRNA transduction. In addition, Peptide-1 decreased Cyclin D1 mRNA expression and increased Caspase-3 mRNA expression. These findings indicate that Peptide-1 can be further investigated as an EGFR L858R-targeting peptide.

Although single-agent chemotherapy is the most common approach for treating platinum-resistant or refractory ovarian cancer (PROC), there is growing evidence that combining molecular targeted agents with chemotherapy is beneficial, especially for certain patient groups. However, the most effective combination regimen remains elusive. This Bayesian network meta-analysis (NMA) aims to identify the best combination therapy for PROC. Relevant studies were searched in PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials from their inception until October 2024. The primary outcomes were overall survival (OS), progression-free survival (PFS) and adverse events (AEs). Statistical analyses were performed using the GEMTC package (1.0-2) and R 4.2.0. This review was registered in PROSPERO (CRD42023428414). Our analysis of 22 randomized controlled trials (RCTs) ( n = 3408) demonstrated that chemotherapy combinations with bevacizumab (hazard ratio (HR) = 0.52-0.65), sorafenib (HR = 0.65, 95% confidence interval (CI): 0.45-0.93) or adavosertib (HR = 0.56, 95%CI: 0.35-0.90) significantly improved OS and PFS versus chemotherapy alone. Notably, adavosertib + gemcitabine was associated with an increased risk of grade 3-4 AEs (relative risk (RR) = 1.8, 95%CI: 1.3-2.7), but these were generally manageable. Bevacizumab-based combinations demonstrate consistent benefits across multiple regimens for PROC. Paclitaxel + bevacizumab emerges as the optimal balance of efficacy and safety. Topotecan + sorafenib could be an alternative for patients who are ineligible for anti-angiogenic therapy. Targeted therapy + chemotherapy may be superior to standalone chemotherapy in PROC.Gemcitabine + bevacizumab can improve PFS of PROC patients.While effective, adavosertib + gemcitabine is associated with increased toxicity, requiring careful patient selection.

27-Hydroxycholesterol (27-HC), as a major cholesterol metabolite, has been shown to be associated with tumor biology, but its role in ovarian cancer remains unclear. This study integrates network toxicology, multi-cohort transcriptomic validation, and single-cell RNA sequencing to systematically investigate the potential role of 27-HC in ovarian cancer and identify key molecular mediators. Among 51 overlapping targets, MMP9 was identified as a robust candidate and consistently validated in independent datasets. Single-cell analysis revealed that MMP9 exhibited distinct expression patterns across different cell populations and was associated with extracellular matrix-related processes. Molecular docking and dynamic simulations confirmed a stable interaction between 27-HC and MMP9. Functionally, 27-HC significantly promoted ovarian cancer cell proliferation, cell cycle progression, and malignant phenotypes in vitro, and facilitated tumor growth in vivo. Concurrently, 27-HC treatment significantly upregulated MMP9 expression at both the mRNA and protein levels in ovarian cancer cells. In summary, these findings provide evidence supporting a potential role of 27-HC in ovarian cancer and its association with MMP9 upregulation, highlighting MMP9 as a potential mediator linking cholesterol metabolism to tumor progression.

Metal complexes possess unique spatial coordination frameworks and tunable biological functions, rendering them promising candidates for antitumor drug development. Herein, we rationally designed and synthesized a novel copper(II) complex Cu1 with the molecular formula Cu1(Cu(L)₂(ClO₄)₂·2H₂O, C₃₆H₂₆Br₂Cl₂CuN₈O₁₀S₂, where the ligand L corresponds to 2-([2,2':6',2″-terpyridin]-4'-yl)-4-bromothiazole. We systematically characterized its antitumor potency toward triple-negative breast cancer (TNBC) and dissected the underlying immunomodulatory mechanisms. UV-vis absorption titration and viscosity assays validated that Cu1 binds tightly to duplex DNA primarily via an intercalative binding mode. In cellular experiments, Cu1 exhibited potent cytotoxicity against both MDA-MB-231 and 4T1 cells, accompanied by pronounced nuclear accumulation and DNA damage. Mechanistically, Cu1 triggered massive intracellular reactive oxygen species (ROS) accumulation, activated the cGAS-STING axis coupled with endoplasmic reticulum (ER) stress, and elicited canonical immunogenic cell death (ICD), as validated by calreticulin (CRT) membrane translocation, HMGB1 cytoplasmic release, and elevated extracellular ATP secretion. Furthermore, Cu1 initiated Caspase-1/GSDMD-mediated pyroptosis. In both tumor vaccination and 4T1 orthotopic tumor-bearing mouse models, Cu1 displayed robust in vivo antitumor activity by orchestrating systemic antitumor immunity: it promoted dendritic cell (DC) maturation, boosted intratumoral CD8+ T cell infiltration, diminished immunosuppressive Foxp3+ regulatory T cells (Tregs), and established long-lasting tumor-specific immune memory. Collectively, Cu1 represents a multifunctional copper coordination complex that integrates direct tumoricidal activity and immunoregulatory capacity. This work delivers comprehensive experimental evidence supporting the translational development of copper-based therapeutic agents for TNBC chemoimmunotherapy.

Saccharomyces cerevisiae is a cost-effective eukaryotic chassis for hosting synthetic circuits that include heterologously expressed proteins. The budding yeast has been extensively used across multiple biotechnological sectors, including environmental applications and pharmaceutical production. Here, we describe a rational workflow for the design and implementation of an S. cerevisiae-based screening platform for aromatase inhibitors. The workflow is organized into three main components: (1) the design and construction of an efficient β-estradiol biosensor; (2) the engineering of a yeast expression system for human aromatase (CYP19A1) and cytochrome P450 reductase; and (3) a screening method for identifying aromatase inhibitors and determining the IC₅₀ values of the most effective compounds. The aromatase inhibitors identified using this platform represent potential therapeutic candidates for a specific subtype of breast cancer.

Twenty-seven polyisopentenylated acylphloroglucinols were designed and synthesized through Friedel-Crafts acylation and alkylation reactions. Among these compounds, a C-farnesylated acylphloroglucinol 13b exhibited selective antiproliferative activity against HER2+ breast cancer cells (SKBr3 and JIMT-1) and triple-negative breast cancer (TNBC) cells (MDA-MB-468), with IC₅₀ values ranging from 7.05 to 9.48 μM. Moreover, compound 13b showed low toxicity toward normal breast epithelial cells MCF-10A (CC₅₀ = 20.1 μM), indicating a favorable safety profile with selectivity indices (SI) ranging from 2.1 to 2.9. Mechanistic studies revealed that 13b inhibits breast cancer cell growth by causing G₂/M phase arrest and inducing apoptosis. These findings provide valuable insights for the development of selective antiproliferative agents against breast cancer based on polyisopentenylated acylphloroglucinol scaffold.