Early-onset preeclampsia (EOPE) is a severe pregnancy disorder characterized by placental dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key pathogenic mechanism in EOPE. This study investigated the role of the hypoxia-inducible factor-2α (HIF-2α) and its downstream target, Hypoxia-Inducible Lipid Droplet-Associated protein (HILPDA), in regulating ferroptosis in EOPE placentas.

METHODS:

Placental tissues from EOPE patients and normotensive controls were analyzed for ferroptosis markers (MDA, GSH, ACSL4, Ferroportin-1, GPX4) and HILPDA/HIF-2α expression. In vitro models employed HTR-8/SVneo trophoblasts and primary human trophoblasts. HILPDA was manipulated via siRNA knockdown or CRISPR-Cas9 knockout. HIF-2α was pharmacologically activated using agonists (HIF-2α agonist 2, AKB-6899). Erastin was used to induce ferroptosis. Assessments included CCK-8 assays for viability, C11-BODIPY581/591 staining and flow cytometry for lipid peroxidation, MDA/GSH quantification for ferroptosis levels, qRT-PCR and Western blotting for HILPDA/HIF-α expression.

RESULTS:

EOPE placentas exhibited significantly elevated ferroptosis, with increased MDA, ACSL4, Ferroportin-1; decreased GSH, GPX4, and upregulated expression of both HILPDA and HIF-2α (but not HIF-1α) compared to controls. In vitro, HIF-2α activation triggered HILPDA expression and robust ferroptosis (increased lipid peroxidation, MDA; decreased GSH; reduced viability) in trophoblasts. Crucially, HILPDA knockdown/knockout significantly attenuated ferroptosis sensitivity and protected trophoblast viability against both Erastin and HIF-2α agonist-induced ferroptotic stress. HIF-2α-induced ferroptosis was substantially rescued by HILPDA deficiency.

CONCLUSION:

Our findings identify the HIF-2α/HILPDA axis as a critical regulator of trophoblast ferroptosis in EOPE. HIF-2α, upregulated in EOPE placenta, transcriptionally induces HILPDA, which sensitizes trophoblasts to ferroptotic death. Targeting this signaling pathway represents a promising therapeutic strategy for mitigating placental dysfunction in EOPE.

2025-12-11·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of 3-(Arylamido)pyrazolopyridine HIF-2α Agonists and a Codrug Strategy with Prolyl Hydroxylase Inhibition for Synergistic Treatment of Renal Anemia

Article

作者: Yang, Le ; Wu, Yue ; Liu, Simeng ; Bao, Xiaoqian ; Zhang, Linjian ; Zhang, Xiaojin ; Yang, Fulai ; Yang, Qingyun ; Liu, Jiaming ; Chen, Liwei ; Gao, Yinli ; Li, Xiang

Activation of the hypoxia-inducible factor-2 (HIF-2) pathway represents a promising strategy for the treatment of renal anemia. Here, we identify compound 48 (ZG-2686), a 3-(benzamido)pyrazolopyridine derivative, as a novel and potent HIF-2α agonist (E_max = 375.7 ± 9.7%, EC₅₀ = 0.25 ± 0.05 μM). Molecular dynamics (MD) simulations provided detailed insights into the binding mode of 48 with the HIF-2α/β complex. In cellular assays, 48 synergistically enhanced HIF-2α-dependent EPO gene expression when combined with the clinically approved prolyl hydroxylase domain (PHD) inhibitor Vadadustat. To further exploit this synergy, we designed and synthesized the bifunctional codrug 50 (ZG-2688), linking 48 with Vadadustat. Notably, codrug 50 induced superior upregulation of EPO levels in vivo compared to coadministration of the two individual agents. Together, these findings demonstrate the first rationally designed codrug integrating an HIF-2α agonist and a PHD inhibitor, highlighting a new direction for the development of renal anemia therapies.

2025-10-23·JOURNAL OF MEDICINAL CHEMISTRY

Structure-Based Optimization of HIF-2α Agonists That Synergistically Enhance Erythropoietin Production with PHD Inhibitors

Article

作者: Xu, Dongming ; Wang, Yuanxun ; Wu, Dalei ; Chen, Keming ; Zhang, Hu ; Zhu, Yidong ; Xu, Weiwei ; Jin, Zecheng ; Wan, Xiaobo ; Zhang, Meina ; Ly, Taiwei ; Li, Fengyao ; Li, Liang ; Zhao, Hongyu ; Guo, Mengqi ; Diao, Xiaotong ; Shang, Qinghong ; Song, Chun ; Bai, Zhifang ; Zhang, Yinan ; Mu, Kaijie ; Chen, Xiaoyu ; Zhuang, Jingjing

Hypoxia-inducible factor 2α (HIF-2α) is a crucial transcription factor regulating various physiological processes, including angiogenesis and erythropoiesis. The activity of HIF-2α is mainly controlled through oxygen-dependent protein hydroxylation, mediated by prolyl hydroxylase domain (PHD) enzymes, leading to subsequent HIF-2α ubiquitination and degradation. While several small-molecule PHD inhibitors have already been clinically applied in renal anemia treatment by indirectly activating the HIF-2α pathway, direct HIF-2α agonists remain largely unexplored. Here, we developed derivatives of HIF-2α agonist M1001, identifying SD-10 through molecular/cellular evaluations. By determining its cocrystal structure with the heterodimeric HIF-2 protein complex, we precisely characterized its molecular mechanism of action. Notably, SD-10 exhibited remarkable synergy with Daprodustat, an approved PHD inhibitor, in stimulating erythropoietin (EPO) secretion both in cellular models and animal studies. These findings not only provide insights into HIF-2α activation mechanism, but also offer a promising lead compound for developing innovative treatments for renal anemia.

100 项与 HIF-2α agonists (Shandong University) 相关的药物交易

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