Table_4_Melatonin: Multi-Target Mechanism Against Diminished Ovarian Reserve Based on Network Pharmacology.xlsx

BackgroundDiminished ovarian reserve (DOR) significantly increases the risk of female infertility and contributes to reproductive technology failure. Recently, the role of melatonin in improving ovarian reserve (OR) has attracted widespread attention. However, details on the pharmacological targets and mechanisms of melatonin-improved OR remain unclear.
ObjectiveA systems pharmacology strategy was proposed to elucidate the potential therapeutic mechanism of melatonin on DOR at the molecular, pathway, and network levels.
MethodsThe systems pharmacological approach consisted of target identification, data integration, network construction, bioinformatics analysis, and molecular docking.
ResultsFrom the molecular perspective, 26 potential therapeutic targets were identified. They participate in biological processes related to DOR development, such as reproductive structure development, epithelial cell proliferation, extrinsic apoptotic signaling pathway, PI3K signaling, among others. Eight hub targets (MAPK1, AKT1, EGFR, HRAS, SRC, ESR1, AR, and ALB) were identified. From the pathway level, 17 significant pathways, including the PI3K-Akt signaling pathway and the estrogen signaling pathway, were identified. In addition, the 17 signaling pathways interacted with the 26 potential therapeutic targets to form 4 functional modules. From the network point of view, by regulating five target subnetworks (aging, cell growth and death, development and regeneration, endocrine and immune systems), melatonin could exhibit anti-aging, anti-apoptosis, endocrine, and immune system regulation effects. The molecular docking results showed that melatonin bound well to all hub targets.
ConclusionThis study systematically and intuitively illustrated the possible pharmacological mechanisms of OR improvement by melatonin through anti-aging, anti-apoptosis, endocrine, and immune system regulation effects.

研究背景：卵巢储备功能减退（Diminished ovarian reserve, DOR）会显著升高女性不孕风险，同时也是辅助生殖技术失败的重要诱因。近年来，褪黑素在改善卵巢储备（Ovarian reserve, OR）方面的作用受到广泛关注，但褪黑素改善卵巢储备的药理学靶点与具体分子机制仍不明确。
研究目的：本研究提出一套系统药理学（systems pharmacology）策略，旨在从分子、通路及网络层面阐明褪黑素针对卵巢储备功能减退的潜在治疗机制。
研究方法：该系统药理学研究方法涵盖靶点鉴定、数据整合、网络构建、生物信息学分析与分子对接（molecular docking）五大环节。
研究结果：从分子层面分析，本研究共鉴定出26个潜在治疗靶点，这些靶点参与与卵巢储备功能减退发生相关的多种生物学过程，包括生殖结构发育、上皮细胞增殖、外源性凋亡信号通路、磷脂酰肌醇3-激酶（PI3K）信号通路等。最终筛选得到8个核心靶点（hub targets），分别为丝裂原活化蛋白激酶1（MAPK1）、蛋白激酶B（AKT1）、表皮生长因子受体（EGFR）、HRAS、肉瘤病毒致癌基因同源物（SRC）、雌激素受体α（ESR1）、雄激素受体（AR）以及白蛋白（ALB）。从通路层面来看，共获得17条显著富集通路，包括PI3K-Akt信号通路（PI3K-Akt signaling pathway）与雌激素信号通路（estrogen signaling pathway）等。此外，这17条信号通路与26个潜在治疗靶点相互作用，共同构成4个功能模块。从网络视角而言，褪黑素可通过调控衰老、细胞生长与死亡、发育与再生、内分泌与免疫系统这5个靶点子网，发挥抗衰老、抗凋亡、内分泌调节以及免疫系统调控的作用。分子对接结果显示，褪黑素可与所有核心靶点实现良好结合。
研究结论：本研究系统性且直观地阐释了褪黑素通过抗衰老、抗凋亡、内分泌调节与免疫系统调控作用改善卵巢储备的潜在药理学机制。