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| Effects of PGF2α on Iron Metabolism, Ferroptosis and Autophagy in Luteal Tissue During Different Stages of the Luteal Phase in Sheep (Ovis aries) |
| ZHEN Zhi-Han1, KANG Jia1, YIN Jiang-Yan1, LI Ao1, LI Yu1, YUE Si-Cong1, LIU Xiao-Na1, DUAN Chun-Hui1, WANG Yuan2, LIU Yue-Qin1,*, ZHANG Ying-Jie1,* |
1 College of Animal Science and Technology, Hebei Agricultural University, Baoding 071000, China;
2 Hengshui Zhihao Animal Husbandry Technology Co., LTD./Hebei Mutton Industry Research Institute, Hengshui 053000, China |
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Abstract Prostaglandin F2α (PGF2α) plays a critical role in luteolysis by mediating apoptosis of luteal cells through its receptor. However, PGF2α does not exhibit pro-apoptotic effects on early-stage corpus luteum (CL) cells. Ferroptosis, a recently discovered form of programmed cell death driven by lipid peroxidation and dependent on iron ions, remains unclear in its role during PGF2α-mediated apoptosis of luteal cells at different developmental stages. This study investigated the impacts of PGF2α on iron content, ferroptosis, and autophagy-related gene expression in ovine CL during early, mid, and late luteal phases. Forty-eight synchronized healthy ewes (Ovis aries) were randomly allocated into 6 groups (experimental vs. control for each phase). Experimental groups received 0.15 mg PGF2α on day 5 (early), 9 (mid), and 13 (late luteal phase), while controls received saline at corresponding time points. CL tissues were collected 3 h post-injection for analyses. Results revealed that PGF2α significantly increased iron content throughout the luteal phase (P<0.05). Phase-specific responses were observed: Early-phase PGF2α upregulated anti-ferroptosis genes (SLC7A11, NRF2, FTH1), pro-ferroptosis gene ACSL4, and ferroptosis-related proteins (Ferritin, GPX4, SLC7A11, LC3B, NCOA4), while downregulating GPX4 and HSPA8 (P<0.05). Mid-phase treatment enhanced SLC7A11, ACSL4, ATG5, TPD52, HSPA5, HSPA8, and corresponding proteins, but suppressed NRF2 (P<0.05). Late-phase administration upregulated P53, ACSL4, GPX4, ATG5, HSPA5, HSPA8 genes and GPX4/SLC7A11/LC3B proteins, while downregulating NRF2, FTH1, and Ferritin (P<0.05). Mechanistic analysis revealed temporal regulation patterns: Early-phase PGF2α enhanced antioxidant defenses via SLC7A11/NRF2/FTH1 axis and iron sequestration to resist ferroptosis; mid-phase activated ACSL4-mediated pro-oxidative environment and ATG5-dependent autophagy, accelerating lipid peroxidation; late-phase triggered P53 activation, NRF2 suppression, and ACSL4 amplification, culminating in iron overload and irreversible ferroptosis-driven luteolysis. These findings demonstrate that PGF2α orchestrates sequential regulation of ferroptosis and autophagy pathways to drive CL transition from early antioxidant protection to terminal regression. This study provides theoretical basis for interventions in luteal dysfunction.
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Received: 20 February 2025
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Corresponding Authors:
* Corresponding authors, zhangyingjie66@126.com; liuyueqin66@126.com
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