地高辛抑制HIF-1α以减轻甲状腺眼病的炎症和纤维化
Digoxin inhibits HIF-1α to attenuate inflammation and fibrosis in thyroid eye disease.
摘要(中文译文)
甲状腺眼病（TED）以眼眶炎症和纤维化为特征，缺氧微环境参与其发病机制。本研究旨在确定缺氧诱导因子-1α（HIF-1α）是否介导TED中缺氧诱导的炎症和纤维化，以及HIF-1α抑制剂地高辛是否能抑制这些过程。采用ELISA法检测TED患者（n=12）和健康对照者（n=7）的血清HIF-1α水平。将TED患者来源的原代眼眶成纤维细胞（OFs）经慢病毒转导过表达HIF-1α或暴露于缺氧条件（1% O₂）。通过qRT-PCR、western blotting和ELISA评估炎症及纤维化标志物。检测STAT3磷酸化及GSDME介导的细胞焦亡。测试地高辛（1.5-6 nM）逆转HIF-1α诱导变化的能力。结果显示，TED患者血清HIF-1α显著升高。HIF-1α过表达可重现缺氧诱导的效应，上调IL-6、IL-8、CCL2、CCL8、CXCL1、CXCL2、IL-1β、TIMP1、α-SMA和COL1A1，增加STAT3磷酸化并激活GSDME介导的细胞焦亡。地高辛剂量依赖性抑制HIF-1α驱动的炎症和纤维化反应，降低STAT3磷酸化，并减弱cleaved caspase-3和GSDME-NT的表达。结论：HIF-1α是TED中缺氧诱导炎症和纤维化的关键下游介质，通过STAT3和GSDME介导的细胞焦亡发挥作用。地高辛对HIF-1α的药理学抑制可逆转这些变化，使地高辛成为TED有前景的治疗候选药物。
Abstract
Thyroid eye disease (TED) is characterized by orbital inflammation and fibrosis, with a hypoxic microenvironment implicated in disease pathogenesis. To determine whether hypoxia-inducible factor-1α (HIF-1α) mediates hypoxia-induced inflammation and fibrosis in TED, and whether the HIF-1α inhibitor digoxin suppresses these processes. Serum HIF-1α was measured by ELISA in TED patients (n = 12) and healthy controls (n = 7). Primary orbital fibroblasts (OFs) from TED patients were transduced with lentiviral HIF-1α or exposed to hypoxia (1% O). Inflammatory and fibrotic markers were assessed by qRT-PCR, western blotting, and ELISA. STAT3 phosphorylation and GSDME-mediated pyroptosis were examined. Digoxin (1.5-6 nM) was tested for its ability to reverse HIF-1α-induced changes. Serum HIF-1α was significantly elevated in TED patients. HIF-1α overexpression recapitulated hypoxia-induced effects, upregulating IL-6, IL-8, CCL2, CCL8, CXCL1, CXCL2, IL-1β, TIMP1, α-SMA, and COL1A1, increasing STAT3 phosphorylation and activating GSDME-mediated pyroptosis. Digoxin dose-dependently suppressed HIF-1α-driven inflammatory and fibrotic responses, reduced STAT3 phosphorylation, and attenuated cleaved caspase-3 and GSDME-NT expression. HIF-1α is a critical downstream mediator of hypoxia-induced inflammation and fibrosis in TED, acting through STAT3 and GSDME-mediated pyroptosis. Pharmacological inhibition of HIF-1α by digoxin reverses these changes, positioning digoxin as a promising therapeutic candidate for TED.
如何引用
AMA
Jie Ling, Chengzhen Gong, Huijing Ye, Mingjun Tang, Dongliang Wang, Xiuyun Gao, et al. Digoxin inhibits HIF-1α to attenuate inflammation and fibrosis in thyroid eye disease.. Biochemical and biophysical research communications. 2026; doi:10.1016/j.bbrc.2026.154287.
APA
Jie Ling, Chengzhen Gong, Huijing Ye, Mingjun Tang, Dongliang Wang, Xiuyun Gao, et al (2026). Digoxin inhibits HIF-1α to attenuate inflammation and fibrosis in thyroid eye disease.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2026.154287
GB/T 7714
Jie Ling, Chengzhen Gong, Huijing Ye, Mingjun Tang, Dongliang Wang, Xiuyun Gao, et al. Digoxin inhibits HIF-1α to attenuate inflammation and fibrosis in thyroid eye disease.[J]. Biochemical and biophysical research communications, 2026 doi:10.1016/j.bbrc.2026.154287.
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