Deficiency of vitamin D-binding protein exacerbates liver fibrosis by disrupting iron homeostasis via the activation of YAP signaling

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Qing Zheng , Qingquan Tan , Dan Wang , Yanling Ma , Yanni Zhou , Yonghua Chen , Dan Long , Jiayin Yang , Li Feng
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Abstract

Liver fibrosis is a chronic progressive disease that can advance to cirrhosis or hepatocellular carcinoma if untreated. While liver transplantation remains the only curative option for end-stage fibrosis, the development of alternative therapies is urgently needed. In this study, we investigated the role of vitamin D-binding protein (VDBP) in hepatic fibrosis using clinical samples and a CCl4-induced mouse model. We observed significant downregulation of VDBP in fibrotic human and murine livers, suggesting that VDBP may serve as a potential biomarker for disease progression. VDBP knockout (VDBP-KO) mice exhibited exacerbated fibrosis, iron overload, and ferroptosis activation, accompanied by dysregulation of the Hippo-YAP pathway. In vitro, VDBP overexpression reversed these effects, while in vivo treatment with the YAP inhibitor verteporfin attenuated fibrosis, normalized iron homeostasis, and suppressed ferroptosis in VDBP-KO mice. Our findings demonstrate that VDBP plays a pivotal role in maintaining iron balance, inhibiting YAP signaling, and preventing ferroptosis during fibrogenesis. Elucidating the molecular mechanisms of VDBP and its downstream pathways may provide novel therapeutic targets for liver fibrosis. This could significantly improve the clinical management of hepatic fibrosis and offer new hope for patients suffering from this debilitating disease.
维生素d结合蛋白缺乏通过激活YAP信号破坏铁稳态,从而加剧肝纤维化
肝纤维化是一种慢性进行性疾病,如果不治疗,可发展为肝硬化或肝细胞癌。虽然肝移植仍然是终末期纤维化的唯一治疗选择,但迫切需要开发替代疗法。在这项研究中,我们通过临床样本和ccl4诱导的小鼠模型研究了维生素d结合蛋白(VDBP)在肝纤维化中的作用。我们在纤维化的人类和小鼠肝脏中观察到VDBP的显著下调,这表明VDBP可能是疾病进展的潜在生物标志物。VDBP敲除(VDBP- ko)小鼠表现出纤维化加剧、铁超载和铁凋亡激活,并伴有Hippo-YAP通路失调。在体外,VDBP过表达逆转了这些作用,而在体内,YAP抑制剂维替波芬可减轻VDBP- ko小鼠的纤维化,使铁稳态正常化,并抑制铁下垂。我们的研究结果表明,VDBP在维持铁平衡、抑制YAP信号和防止纤维形成过程中的铁下垂中起关键作用。阐明VDBP的分子机制及其下游通路可能为肝纤维化的治疗提供新的靶点。这将显著改善肝纤维化的临床管理,并为患有这种使人衰弱的疾病的患者带来新的希望。
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
期刊介绍: Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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