Xiao-Yong Zhu

This Correspondence is a formal response to the Comment by Dr. Machado regarding our publication “Creatine Promotes Endometriosis by Inducing Ferroptosis Resistance via Suppression of PrP.” We address several conceptual concerns raised in the Comment and clarify the physiological relevance of creatine concentrations, the methodological framework for PrP target identification, and the interpretation of human cohort data. We further provide evidence supporting creatine accumulation in endometriotic lesions and peritoneal fluid, and clarify the experimental basis for PrP target identification using integrated biochemical, computational, and functional analyses. Rather than demonstrating a direct molecular interaction, our findings instead provide convergent evidence consistent with PrP acting as a candidate functional target of creatine. We also reinforce the association between creatine exposure, ferroptosis resistance, and lesion progression, while acknowledging that definitive biochemical validation of direct binding remains to be established. Importantly, our study provides translational support for mechanistic investigations in endometriosis, rather than establishing a definitive clinical biomarker. Collectively, we highlight the metabolic significance of creatine–PrP signaling in endometriosis and discuss future directions for mechanistic and clinical validation.

Background: Decidual macrophages maintain immune tolerance and support decidualization at the maternal–fetal interface. However, the heterogeneity and functions of macrophage subsets in recurrent spontaneous abortion (RSA) remain unclear. Methods: We integrated single-cell RNA sequencing of human endometrium and decidua with clinical validation. Functional assays using THP-1–derived macrophages and the co-culture with decidual stromal cells were performed to characterize macrophage subsets and investigate their roles in decidualization and RSA pathogenesis. Results: A subset of FOLR2 ⁺ macrophages enriched in the decidua showed an M2-like immunoregulatory phenotype. In RSA decidua, FOLR2 expression and the proportion of FOLR2 ⁺ macrophages were markedly reduced, accompanied by increased inflammatory signaling and impaired angiogenic and adhesion interactions. Functional assays showed that FOLR2 overexpression enhanced immunoregulatory, tissue-resident, and pro-angiogenic properties, whereas FOLR2 silencing promoted inflammatory responses and impaired angiogenesis. Reciprocal crosstalk between DSCs and FOLR2 ⁺ macrophages established a positive feedback loop that promoted stromal decidualization and supported pregnancy maintenance. Conclusions: FOLR2 ⁺ macrophages represent an immunoregulatory subset at the maternal–fetal interface with tissue-resident and pro-angiogenic features. The loss of FOLR2 ⁺ macrophages in RSA may contribute to immune dysregulation and defective decidualization, providing new insights into the immune mechanisms underlying RSA pathogenesis.

Fertility-sparing surgery (FSS) is a key therapeutic strategy for borderline ovarian tumors (BOTs) in young women. However, the optimal surgical approaches and the prognostic significance of clinicopathological features remain a subject of debate. This study aimed to evaluate the oncological safety and reproductive outcomes following FSS in a large cohort of young BOT patients. We retrospectively reviewed 533 patients (aged 20-40 years) diagnosed with BOTs who underwent FSS at a single academic medical center between 2010 and 2021. Survival outcomes were estimated using the Kaplan-Meier method. To identify independent prognostic factors for recurrence, variable selection was performed using the Least Absolute Shrinkage and Selection Operator regression, followed by multivariable Cox proportional hazards analysis with backward elimination. Over a median follow-up of 61.90 months (range: 1.03-176.53months), 85 (15.95%) patients experienced recurrence, comprising 77 (14.45%) borderline recurrences and 8 (1.50%) invasive transformation. The 5-year and 10-year disease-free survival rates were 82.0% and 75.9%, respectively. Multivariable analysis identified bilateral ovarian lesions (HR 2.07, p = 0.017), exophytic growth (HR 3.66, p < 0.001), intraepithelial carcinoma (HR 4.23, p = 0.004), and FIGO stage III (HR 2.23, p = 0.014) as independent prognostic risk factors for recurrence. Notably, peritoneal biopsy was associated with a significantly lower recurrence risk (HR 0.42, p = 0.004). Histological stratification revealed that for serous BOTs, exophytic growth (HR 4.05, p < 0.001), cystectomy (HR 3.03, p = 0.008), FIGO stage III (HR 2.46, p = 0.011) were risk factors, while peritoneal biopsy (HR 0.44, p = 0.018) remained protective. For MBOT, intraoperative chromotubation was identified as a risk factor (HR 8.62, p < 0.001). Among 176 patients attempting conception, the live birth rate was 70.45%. In those utilizing assisted reproductive technology (n = 31), the pregnancy and live birth rates were 77.42% and 48.39%, respectively. FSS is oncologically safe and offers favorable reproductive outcomes for young women with BOTs. The identified prognostic factors were instrumental in tailoring individualized surveillance and management strategies.

Recurrent pregnancy loss (RPL) is a multifactorial condition characterized by the loss of two or more consecutive pregnancies, affecting approximately 1-2% of couples attempting to conceive [1,2]. ...

Recurrent spontaneous abortion (RSA), defined as the loss of two or more pregnancies before 20 weeks of gestation, remains a challenging clinical problem with largely unknown pathogenesis. In this study, we performed single-cell RNA sequencing analysis of control and RSA villous tissues and identified three subtypes of cytotrophoblasts (CTBs): CTB1, which is mainly involved in protein synthesis; CTB2, a highly proliferative progenitor population; and CTB3, an adhesive and invasive subtype that serves as the precursor of extravillous trophoblasts. We also characterized syncytiotrophoblasts, which are responsible for hormone production. In RSA villi, the functions of both CTBs and syncytiotrophoblasts were impaired. Notably, CTB2 and CTB3 exhibited pronounced features of cellular senescence, potentially contributing to reduced proliferative and differentiation capacity. These findings suggest that aberrant trophoblast senescence may underlie defective placentation in RSA and highlight potential therapeutic targets for restoring trophoblast function and improving pregnancy outcomes.

In brief: Endometriosis (EM) is a chronic inflammatory disease with unclear pathogenesis, in which peritoneal macrophages play a pivotal role. This study demonstrates that creatine (CR) induces M2 polarization of peritoneal macrophages, promoting angiogenesis, fibrogenesis and lesion progression in EM, offering new insight into potential therapeutic strategies. EM is a chronic inflammatory disease characterized by the growth of endometrium-like tissues outside the uterine cavity, with an unclear pathogenesis. The analysis of single-cell sequencing data revealed the pivotal role of peritoneal macrophages in the development of EM. We noted significant CR enrichment and synthesis in peritoneal macrophages of patients with EM compared with women without EM. To further investigate the mechanisms of CR in EM, we performed RNA sequencing and in vitro experiments. We found that CR reprograms M2 polarization by enhancing matrix metalloproteinases and anti-inflammatory cytokines, which are involved in angiogenesis, fibrogenesis, cell adhesion and tissue repair. The coculture of CR-treated macrophages promoted the migration and fibrogenesis of endometrial stromal cells, as well as the angiogenesis of HUVECs in vitro . In summary, this article reveals that CR might polarize M2 macrophages, promoting the initiation, fibrosis and angiogenesis of ectopic endometrial lesions, ultimately resulting in the development of EM. These findings underscore the crucial immunomodulatory role of CR in the pathogenesis of EM, offering a promising target for therapeutic intervention.

Endometriosis, a chronic inflammatory disease, significantly impairs the quality of life of women in their reproductive years; however, its pathogenesis remains poorly understood. The accumulation of retrograde menstruation and recurrent bleeding fosters a high‐iron environment in ectopic lesions, triggering ferroptosis in ectopic endometrial stromal cells (EESCs), thereby hindering the establishment of endometriosis. However, abnormal EESCs demonstrate resistance to ferroptosis in high‐iron environments, promoting the progression of this disease. Here, novel findings on the accumulation of creatine, derived from endogenous synthesis, in both peritoneal fluid and EESCs of patients with endometriosis are presented. Creatine supplementation reduces cellular iron concentrations, mitigating oxidative stress and lipid peroxidation, thereby enhancing cell viability and preventing ferroptosis under high‐iron conditions. Utilizing the drug affinity–responsive target stabilization (DARTS) assay, prion protein (PrP) as a potential creatine‐sensing protein is identified. Mechanistically, creatine binds to the active site of PrP, inhibits the conversion of trivalent iron to divalent iron, and decreases iron uptake, promoting the tolerance of EESCs to ferroptosis. This interaction contributes to the development of endometriosis. The novel association between creatine and ferroptosis provides valuable insights into the role of creatine in endometriosis progression and highlights its potential as a therapeutic target for endometriosis.

Purpose: To examine the potential association between polycystic ovary syndrome (PCOS) and hyperuricemia and to elucidate the underlying contributory factors.Methods: Retrospective study on 603 women with PCOS and 604 women without PCOS. Anthropometric features, reproductive hormone profiles, and metabolic parameters were measured and compared between two groups of patients. Examinations of correlations between SUA levels and other parameters were conducted to discern potential correlations.Results: Both serum uric acid levels and the incidence of hyperuricemia exhibited statistically significant elevations in women with PCOS when compared to their counterparts without PCOS. Nonetheless, this statistical difference was not found between the obese subgroup after stratifying study subjects by body mass index (BMI). Pearson’s correlation analysis underscored the prominence of BMI as a robust factor influencing SUA levels in women, regardless of their PCOS status. Furthermore, multivariable linear regression model demonstrated significant positive associations between SUA levels and several variables, namely dehydroepiandrosterone sulfate (DHEA-S), free androgen index (FAI), total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), area under the curve for insulin (AUC-I), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Additionally, it is noteworthy that the prevalence of hyperuricemia exhibited a positive association with fasting plasma glucose (FPG) levels, while conversely, it displayed a negative association with estradiol (E2) levels.Conclusions: PCOS is associated with a significant elevation of SUA level and hyperuricemia prevalence. HA, IR, and dyslipidemia may be the mediators in the pathogenesis of hyperuricemia in women with PCOS.