Phoenixin-14 Alleviates Premature Ovarian Failure by Inhibiting Ferroptosis Through SLC7A11/GPX4

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL
Rong Wu, Ting Wang, Xiaofeng Xu, Ying Wang, Jingjing Hu, Wenjuan Yang, Xiao Wu, Zhaolian Wei
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Abstract

Premature ovarian failure (POF) is a complex condition marked by early ovarian decline, reduced follicular reserve, and compromised oocyte quality. Oxidative stress (OS) and ferroptosis are critical drivers of POF progression. This study investigates the therapeutic potential of Phoenixin-14 (PNX-14) in alleviating POF in rats by modulating granulosa cell (GC) ferroptosis through the ATF4/SLC7A11/GPX4 signaling pathway. Cisplatin-induced POF rat models were used to evaluate PNX-14's effects on ovarian function, oxidative stress (MDA/SOD), and ferroptosis. Serum PNX-14 levels, GPR173 expression, body/ovarian weights, follicle development, and oxidative markers were analyzed. In cisplatin-induced POF rat models, serum PNX-14 levels and GPR173 expression were significantly downregulated, suggesting potential impairment of the PNX-14/GPR173 axis. PNX-14 administration improved body and ovarian weights, restored ovarian tissue structure, and reduced oxidative damage, as evidenced by reduced MDA levels and enhanced SOD activity. At the molecular level, PNX-14 suppressed ferroptosis in GCs by enhancing ATF4 expression, which in turn upregulated SLC7A11 and GPX4, critical components of cellular antioxidant defense. Caspase-3 assays suggested minimal apoptosis in cisplatin-treated cells. PNX-14 showed similar effectiveness to Fer-1 in reducing cisplatin-induced ferroptosis, evidenced by restored viability, lower Fe²⁺, and reduced MDA, without added benefit when combined. Silencing ATF4 reversed the beneficial effects of PNX-14 on GC viability and ferroptosis, confirming the pivotal role of ATF4 in mediating the protective effects of PNX-14. These results suggest that PNX-14 alleviates POF by inhibiting GC ferroptosis through the ATF4/SLC7A11/GPX4 axis, providing a potential therapeutic strategy for POF management.

Phoenixin-14通过SLC7A11/GPX4抑制铁下垂缓解卵巢早衰
卵巢早衰(POF)是一种复杂的疾病,其特征是卵巢功能早期衰退,卵泡储备减少,卵母细胞质量受损。氧化应激(OS)和铁下垂是POF进展的关键驱动因素。本研究探讨了凤凰素-14 (phoenix -14, PNX-14)通过ATF4/SLC7A11/GPX4信号通路调节颗粒细胞(GC)铁凋亡,减轻大鼠POF的治疗潜力。采用顺铂诱导的POF大鼠模型,评价PNX-14对卵巢功能、氧化应激(MDA/SOD)和铁吊的影响。分析血清PNX-14水平、GPR173表达、体/卵巢重量、卵泡发育和氧化标志物。在顺铂诱导的POF大鼠模型中,血清PNX-14水平和GPR173表达显著下调,提示PNX-14/GPR173轴可能受损。PNX-14改善了机体和卵巢重量,恢复了卵巢组织结构,减少了氧化损伤,这可以通过降低MDA水平和增强SOD活性来证明。在分子水平上,PNX-14通过增强ATF4表达来抑制GCs中的铁凋亡,从而上调细胞抗氧化防御的关键成分SLC7A11和GPX4。Caspase-3检测显示,顺铂处理的细胞凋亡最小。PNX-14在减少顺铂诱导的铁下垂方面表现出与Fe -1相似的有效性,通过恢复活力、降低Fe 2 +和降低MDA来证明,联合使用时没有额外的益处。沉默ATF4逆转了PNX-14对GC活力和铁凋亡的有益作用,证实了ATF4在介导PNX-14保护作用中的关键作用。这些结果表明PNX-14通过ATF4/SLC7A11/GPX4轴抑制GC铁下垂来缓解POF,为POF的治疗提供了一种潜在的治疗策略。
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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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