Shishi Li

Background: Lactate is increasingly recognized not only as a metabolic end product of glycolysis but also as a signaling metabolite that links metabolic reprogramming to epigenetic and transcriptional regulation through protein lactylation. Emerging evidence suggests that the lactate–lactylation axis contributes to the pathogenesis of female reproductive diseases, including endometriosis, endometrial cancer, polycystic ovary syndrome, and ovarian cancer. Main body: This review summarizes current evidence on lactate production, lactate transport, and histone/non‐histone lactylation in female reproductive diseases. Available studies indicate that aberrant lactate accumulation and lactylation may influence chromatin accessibility, transcription factor activity, immune remodeling, ferroptosis resistance, steroidogenic dysfunction, and DNA damage repair. These processes may contribute to disease progression and may provide candidate biomarkers or therapeutic targets, including lactylation‐related enzymes, lactate transporters, glycolytic regulators, and lactate‐depleting strategies. However, the current evidence base remains dominated by cell and animal studies, and major barriers persist, including incomplete identification of bona fide reader proteins, insufficient standardization of site‐specific lactylation detection, limited validation in human cohorts, and uncertainty regarding disease specificity. Conclusion: The lactate–lactylation axis provides a useful framework for understanding metabolic–epigenetic coupling in female reproductive diseases and may inform future biomarker development, patient stratification, and mechanism‐based therapeutic strategies.

Bone homeostasis mainly depends on the equilibrium of osteoclasts and osteoblasts, overactivated osteoclasts play a pivotal role in the progression of osteoporosis. Here, we revealed that Pla2g7 (phospholipase A2 group VII) was positively correlated with bone resorption in clinic. By single-cell RNA-seq data analysis, Pla2g7 was found highly enriched in osteoclasts along the developmental trajectory, which promoted osteoclast differentiation. Inhibition of Pla2g7 by Darapladib impaired both human and mice osteoclast differentiation, meanwhile, Pla2g7-deficient mice showed higher bone mass and restored the ovariectomy-induced bone loss. Mechanistically, we identified that Alox12 (arachidonate 12-lipoxygenase) mediated-arachidonic acid metabolism is a key determinant in Pla2g7 enhanced osteoclast differentiation. Its metabolite 12-HETE (12-hydroxyeicosatetraenoic acid) activated Gpr31 to regulate osteoclast formation via p38 MAPK pathway and mitochondrial energy metabolism. Collectively, our study uncovers an Alox12/12-HETE/Gpr31 axis that regulates Pla2g7-induced osteoclast differentiation, and provides a new insight for osteoporosis treatment.

To investigate whether repeating laser-assisted hatching (LAH) procedure on day 6 low-grade cleavage-stage embryos (LGCEs) helps blastulation. A total of 579 cycles with LGCEs from 2019 to 2022 was retrospectively reviewed. In 323 cycles, single LAH producing small holes (10 μm) was performed on LGCEs on day 4 (D4-LAH). In 256 cycles with persistent LGCEs despite D4-LAH, a repeat LAH procedure was performed on day 6 (Dual-LAH) with a bigger hole (30 μm). We compared day 7 blastocyst formation rate, usable blastocyst rate, and good grade blastocyst rate from these day 6 LGCEs between the two groups. Compared to the D4-LAH group, the Dual-LAH group had both higher day 7 blastocyst formation rate (9.4% vs. 3.0%, p < 0.001) and higher day 7 usable blastocyst rates (7.4% vs. 2.1%, p < 0.001). For persistent LGCEs despite single LAH, performing a repeat LAH on day 6 increased day 7 blastocyst formation rate.

Endometriosis is one of the most common disorders that causes infertility in women. Iron is overloaded in endometriosis peritoneal fluid (PF), with harmful effects on early embryo development. However, the mechanism by which endometriosis peritoneal fluid affects embryonic development remains unclear. Hence, this study investigated the effect of iron overload on mouse embryos and elucidated the molecular mechanism. Iron overload in endometriosis PF disrupted blastocyst formation, decreased GPX4 expression and induced lipid peroxidation, suggesting that iron overload causes embryotoxicity and induces ferroptosis. Moreover, mitochondrial damage occurs in iron overload-treated embryos, presenting as decreased ATP levels, increased ROS levels and MMP hyperpolarization. The cytotoxicity of iron overload is attenuated by the ferroptosis inhibitor Fer-1. Furthermore, Smart-seq analysis revealed that HMOX1 is upregulated in embryo ferroptosis and that HMOX1 suppresses ferroptosis by maintaining mitochondrial function. This study provides new insight into the mechanism of endometriosis infertility and a potential target for future endometriosis infertility treatment efforts.

Background: Laser-assisted hatching (LAH) has been widely applied to facilitate blastocyst hatching in IVF-ET treatment, however, the effect of LAH on subsequent development and clinical outcomes of the lower grade cleavage stage embryos (LGCE) remains unknown. Our study aimed at evaluating the effect of LAH on blastocyst formation and the clinical pregnancy outcomes of LGCE embryos after transfer. Methods: A total of 608 cycles of IVF/ICSI treatment from November 2017 to September 2019 were included in our study as follows: 296 in the LAH group and 312 in the N-LAH group. The total blastocyst rate, usable blastocyst rate, good-grade blastocyst rate and clinical pregnancy rate were statistically compared between the two groups. Results: The total blastocyst rate (50.7% vs 40.2%, P < 0.001), usable blastocyst rate (31.0% vs 18.6%, P < 0.001) were significantly higher in the LAH group than those in the N-LAH group. After analysis of generalized estimating equations, LAH was positively correlated with the blastocyst rate (B = 0.201, OR 95% CI = 1.074–1.393, P = 0.002), usable blastocyst rate (B = 0.478, OR 95% CI = 1.331–1.955, P < 0.001). However, the clinical pregnancy rate after blastocyst transfer did not differ between LAH group and N-LAH group (49.4% vs 40.0%, P > 0.05, respectively). Conclusions: A higher proportion of total blastocysts and usable blastocysts can be obtained by LAH in LGCE, which may be beneficial to the outcome of the IVF/ICSI-ET cycle.