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.

背景：卵巢储备功能减退（DOR）显著增加了女性不孕的风险，并导致生殖技术失败。近期，褪黑素在改善卵巢储备（OR）方面的作用引起了广泛关注。然而，褪黑素改善卵巢储备的药理靶点和作用机制仍不明确。研究目的：本研究提出了一种系统药理学策略，旨在阐明褪黑素对DOR在分子、通路和网络水平上的潜在治疗机制。研究方法：系统药理学方法包括靶点识别、数据整合、网络构建、生物信息学分析和分子对接。研究结果：从分子层面，确定了26个潜在的治疗靶点，它们参与与DOR发展相关的生物学过程，如生殖结构发育、上皮细胞增殖、外源性凋亡信号通路、PI3K信号通路等。确定了8个关键靶点（MAPK1、AKT1、EGFR、HRAS、SRC、ESR1、AR和ALB）。从通路层面，确定了17个显著通路，包括PI3K-Akt信号通路和雌激素信号通路。此外，这17个信号通路与26个潜在治疗靶点相互作用，形成了4个功能模块。从网络视角，褪黑素通过调节五个靶点子网络（衰老、细胞生长与死亡、发育与再生、内分泌和免疫系统）来发挥抗衰老、抗凋亡、内分泌和免疫系统调节作用。分子对接结果显示，褪黑素与所有关键靶点结合良好。研究结论：本研究系统性地直观地阐述了褪黑素通过抗衰老、抗凋亡、内分泌和免疫系统调节作用改善卵巢储备的潜在药理机制。