[Role of hyaluronic acid synthases in female infertility-related diseases]

Lin Liu, Yidan Liu, Ting Wang, Qiuyao Li, Xinyi Zhang, Qingyu Liu
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025 · vol. 50(11) , pp. 2115–2123 · doi:10.11817/j.issn.1672-7347.2025.250477 · PMID:41656845 · PMC12949929
review OA: gold public-domain-us
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Hyaluronic acid synthases (HAS) regulate critical female reproductive processes and their abnormal expression is linked to infertility-related diseases like PCOS, endometriosis, and premature ovarian insufficiency.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 · read from full text ⓘ

The paper reviews the biological roles of hyaluronic acid (HA) synthases HAS1, HAS2, and HAS3 in female infertility-related conditions, outlining how HA—through receptors such as CD44 and RHAMM—regulates ovarian follicle development, oocyte maturation, cumulus expansion, luteal function, and embryo implantation. It synthesizes evidence that HAS2 is particularly important, citing studies where altered HAS2/HA (from genetic factors, growth factor signaling, or toxic exposures) is associated with impaired oocyte quality, abnormal ovulation, and defective endometrial adhesion, while also noting mechanistic gaps where human data are limited by ethics. The review reports associations between HA/HAS dysregulation and multiple diseases (including EMS, PCOS, POI, RPL, and RIF) and discusses caveats such as unresolved discrepancies across studies on HAS2 and oocyte quality. Relevance to endometriosis: the paper is heavily focused on HA/HAS in endometriosis, describing increased lesion HA and HAS2 expression in EMS, functional inhibition of HAS2 to reduce lesion invasion, and animal-model findings where HA or HAS2 modulation affects implantation and vascularization in endometriosis models.

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Abstract

The hyaluronic acid synthase (HAS) family participates in key physiological processes such as follicular development, oocyte maturation, ovulation, and embryo implantation by regulating the synthesis of hyaluronic acid, and plays an important role in the female reproductive system. In recent years, studies have found that the HAS family exerts important regulatory effects in female infertility-related diseases. HAS2 plays a critical role in cumulus expansion and oocyte maturation, and abnormal expression of HAS2 may lead to impaired cumulus expansion and ovulatory disorders. HAS1 and HAS3 are associated with ovarian dysfunction and decreased endometrial receptivity. In addition, abnormal expression of the HAS family is closely related to infertility-related diseases such as polycystic ovary syndrome, endometriosis, and premature ovarian insufficiency. Systematic elucidation of the roles of the HAS family will not only help to deepen the understanding of the pathological mechanisms of female infertility-related diseases, but is also expected to provide key theoretical evidence and precise interventional targets for the development of novel diagnostic biomarkers, optimization of ovulation induction protocols, and improvement of embryo implantation success rates, ultimately promoting the individualized diagnosis and treatment of female infertility.
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结

HAS家族在女性不孕相关疾病中的研究已取得显著进展，揭示了其在卵母细胞成熟、胚胎着床、卵巢功能及子宫相关疾病中的关键作用。HAS家族的异常表达还与PCOS、EMS、POI等多种不孕相关疾病密切相关。然而，目前对HAS家族的作用机制尚未完全明确，其作为诊断标志物和治疗靶点的潜力仍处于探索阶段。未来研究需进一步深入探究HAS家族的分子机制，结合多学科交叉手段，挖掘其在疾病中的具体功能及调控网络，并推动基础研究成果向临床应用转化，开发特异性诊断标志物和治疗策略，为改善女性生殖健康提供新的临床思路和诊疗方案。

Section

复发性流产(recurrent pregnancy loss，RPL)是指妊娠20~24周之前2次或2次以上临床确认的妊娠失败，包括胚胎和胎儿丢失，约2.5%的备孕女性经历过这种情况 [ 74 ] 。HA在着床和胎盘形成中起重要作用，HA的高水平和成熟状态有利于维持正常妊娠。研究 [ 75 ] 表明，HA及其合成酶HAS2在维持早期妊娠中发挥关键作用。与正常妊娠相比，不明原因流产患者的绒毛组织中HA含量及HAS2表达显著降低，而正常胎盘中HA的积累可能与HAS2活性增强相关，后者促进高分子量HA的合成，从而支持滋养细胞功能及胎盘发育。此外，正常妊娠的蜕膜基质细胞中HAS2的表达和分泌的高分子量HA远高于不明原因流产者的HA，这意味着母胎界面处较高水平的高分子量HA可通过调控蜕膜基质细胞的增殖和凋亡，维持妊娠微环境的稳定性 [ 76 ] 。综上所述，母胎界面HA-HAS2调控网络的异常可能导致滋养层-蜕膜相互作用失调，进而参与不明原因流产的病理过程。 反复种植失败(recurrent implantation failure，RIF)由多因素导致，目前被广泛接受的RIF的定义是指在女性年龄小于40岁的情况下，经过至少3个周期的至少4枚优质卵裂期胚胎移植后仍未能实现临床妊娠 [ 77 ] 。本课题组前期研究 [ 78 ] 发现，RIF患者中的甲基化相关酶的含量与健康育龄女性相比显著变化，如 ALKBH5 、 YTHDF3 等，进一步分析发现RIF患者中HAS2的表达及 m6A 甲基化水平显著降低，且HAS2在子宫内膜基质细胞中有促进增殖和抑制衰老的作用。以上结果说明HAS2及其m6A甲基化修饰与子宫内膜容受性和胚胎植入密切相关，但其在RIF患者子宫内膜中的潜在作用研究较少，仍需深入研究其作用机制。

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Condition tags

mesh:D004715endometriosisinfertility

MeSH descriptors

Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases Hyaluronan Synthases

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europepmc
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pmc
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