Biochemical and biophysical research communications · 2026
Digoxin inhibits HIF-1α to attenuate inflammation and fibrosis in thyroid eye disease.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Ling Jie, Gong Chengzhen, Ye Huijing, Tang Mingjun, Wang Dongliang, Gao Xiuyun, Xing Chenqi, Wu Guangsen, Li Xinyu, Bi Shaowei, Yang Huasheng, Huang Lijuan, Chen Rongxin
Аннотация
BACKGROUND: Thyroid eye disease (TED) is characterized by orbital inflammation and fibrosis, with a hypoxic microenvironment implicated in disease pathogenesis.
OBJECTIVE: 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.
METHODS: 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% O2). 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
METHODS: 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% O2). 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.
RESULTS: 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.
CONCLUSIONS: 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.