TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
Cell Death Dis. 2024 Sep 17;15(9):680. doi: 10.1038/s41419-024-07063-0.
Iron overload and cellular senescence have been implicated in liver fibrosis, but their possible mechanistic connection has not been explored. To address this, we have delved into the role of iron and senescence in an experimental model of chronic liver injury, analyzing whether an iron chelator would prevent liver fibrosis by decreasing hepatocyte senescence. The model of carbon tetrachloride (CCl) in mice was used as an experimental model of liver fibrosis. Results demonstrated that during the progression of liver fibrosis, accumulation of iron occurs, concomitant with the appearance of fibrotic areas and cells undergoing senescence. Isolated parenchymal hepatocytes from CCl-treated mice present a gene transcriptomic signature compatible with iron accumulation and senescence, which correlates with induction of Reactive Oxygen Species (ROS)-related genes, activation of the Transforming Growth Factor-beta (TGF-β) pathway and inhibition of oxidative metabolism. Analysis of the iron-related gene signature in a published single-cell RNA-seq dataset from CCl-treated livers showed iron accumulation correlating with senescence in other non-parenchymal liver cells. Treatment with deferiprone, an iron chelator, attenuated iron accumulation, fibrosis and senescence, concomitant with relevant changes in the senescent-associated secretome (SASP), which switched toward a more anti-inflammatory profile of cytokines. In vitro experiments in human hepatocyte HH4 cells demonstrated that iron accumulates in response to a senescence-inducing reagent, doxorubicin, being deferiprone able to prevent senescence and SASP, attenuating growth arrest and cell death. However, deferiprone did not significantly affect senescence induced by two different agents (doxorubicin and deoxycholic acid) or activation markers in human hepatic stellate LX-2 cells. Transcriptomic data from patients with different etiologies demonstrated the relevance of iron accumulation in the progression of liver chronic damage and fibrosis, correlating with a SASP-related gene signature and pivotal hallmarks of fibrotic changes. Altogether, our study establishes iron accumulation as a clinically exploitable driver to attenuate pathological senescence in hepatocytes.
铁过载和细胞衰老与肝纤维化有关，但它们之间可能的机制联系尚未被探索。为了解决这个问题，我们深入研究了铁和衰老在慢性肝损伤实验模型中的作用，分析了铁螯合剂是否可以通过减少肝细胞衰老来预防肝纤维化。我们使用四氯化碳（CCl）诱导的小鼠模型作为肝纤维化的实验模型。结果表明，在肝纤维化进展过程中，铁会积累，同时出现纤维化区域和衰老的细胞。从 CCl 处理的小鼠中分离出的实质肝细胞表现出与铁积累和衰老一致的基因转录组特征，这与诱导活性氧（ROS）相关基因、转化生长因子-β（TGF-β）途径的激活和氧化代谢的抑制有关。对 CCl 处理的肝脏中已发表的单细胞 RNA-seq 数据集的铁相关基因特征进行分析表明，铁积累与其他非实质细胞的衰老相关。用铁螯合剂去铁酮治疗可减轻铁积累、纤维化和衰老，同时伴随着衰老相关分泌表型（SASP）的相关变化，使细胞因子向更抗炎的表型转变。在人肝细胞 HH4 细胞的体外实验中，铁在衰老诱导剂阿霉素的作用下积累，去铁酮能够预防衰老和 SASP，减轻生长停滞和细胞死亡。然而，去铁酮对两种不同试剂（阿霉素和脱氧胆酸）或人肝星状细胞 LX-2 细胞中的激活标志物诱导的衰老没有显著影响。来自不同病因的患者的转录组数据表明，铁积累与肝慢性损伤和纤维化的进展有关，与 SASP 相关的基因特征和纤维化变化的关键特征相关。总之，我们的研究确立了铁积累作为一种可临床利用的驱动因素，可减轻肝细胞的病理性衰老。
