PBX1-IL7R轴介导非酒精性脂肪性肝病的肝纤维化。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-08-28 DOI:10.1016/j.lfs.2025.123948

Zhen Yang , Jinbo Zhang , Qihang Wang , Huihui Xu , Xihu Qin , Fangqiao Lv

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引用次数: 0

摘要

目的：非酒精性脂肪性肝病（NAFLD），也被称为代谢功能障碍相关脂肪变性肝病（MASLD），是一系列最终导致肝硬化和肝细胞癌的慢性肝病。肝纤维化是NAFLD的病理特征和促进因素。在本研究中，我们研究了靶向前b细胞白血病转录因子1 （PBX1）和白细胞介素7受体（IL7R）是否可能改善NAFLD背景下的肝纤维化。方法与材料：采用缺胆碱氨基酸高脂饲料（CDAA-HFD）诱导C57/B6j小鼠NAFLD。关键发现：与对照组小鼠相比，喂食CDAA-HFD小鼠分离的肝星状细胞（hsc）中PBX1表达和IL7R表达均上调。通过向小鼠注射携带短发夹RNA （shRNA）的AAV6来消除肌成纤维细胞特异性PBX1，可显著减轻CDAA-HFD喂养引起的肝纤维化。同样，肌成纤维细胞特异性IL7R的缺失显著减轻了肝纤维化。值得注意的是，肝损伤和脂肪变性不受PBX1或IL7R缺失的影响。重要的是，用中和抗体阻断IL7R同样可以减少nafld相关的肝纤维化。最后，在NAFLD患者的肝脏标本中发现PBX1表达、IL7R表达与肌成纤维细胞活化呈正相关。意义：我们的数据证明了靶向PBX1-IL7R轴干预nafld相关肝纤维化的可行性。

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A PBX1-IL7R axis mediates liver fibrosis in non-alcoholic fatty liver disease

Aims

Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction associated steatotic liver disease (MASLD), represents a spectrum of chronic liver diseases that eventually lead to cirrhosis and hepatocellular carcinoma. Liver fibrosis is both a pathological feature and a contributing factor in NAFLD. In the present study we investigated whether targeting pre-B cell leukemia transcription factor 1 (PBX1) and interleukin 7 receptor (IL7R) might ameliorate liver fibrosis in the context of NAFLD.

Methods and materials

NAFLD was induced in C57/B6j mice by feeding with a choline-deficient amino acid defined high-fat diet (CDAA-HFD).

Key findings

Both PBX1 expression and IL7R expression were up-regulated in hepatic stellate cells (HSCs) isolated from the mice fed the CDAA-HFD compared to those isolated from the control mice. Myofibroblast-specific PBX1 depletion, by injecting the mice with AAV6 carrying short-hairpin RNA (shRNA) against PBX1, significantly attenuated liver fibrosis induced by CDAA-HFD feeding. Similarly, myofibroblast-specific IL7R depletion significantly mitigated NAFLD-associated liver fibrosis. Of note, liver injury and steatosis were not influenced by either PBX1 or IL7R depletion. Importantly, IL7R blockade with a neutralizing antibody likewise diminished NAFLD-associated liver fibrosis. Finally, a positive correlation between PBX1 expression, IL7R expression, and myofibroblast activation was identified in liver specimens from NAFLD patients.

Significance

Our data demonstrate the feasibility of targeting the PBX1-IL7R axis for the intervention of NAFLD-associated liver fibrosis.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

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