圣地亚哥德孔波斯特拉大学Ruben Nogueiras团队的研究显示，肝星状细胞缺乏PCK1通过促进三羧酸循环和增加糖酵解导致肝纤维化。2026年2月23日，国际知名学术期刊《细胞—代谢》发表了这一成果。

课题组人员发现PCK1在纤维化动物和纤维化患者的HSC中减少，与纤维化严重程度呈负相关。沉默PCK1可激活人造血干细胞并增加纤维化标志物，而异位PCK1表达可减弱转化生长因子β1 （TGF-β1）诱导的激活。活化的HSC表现出糖酵解和三羧酸（TCA）循环活性升高，但PCK1过表达降低了乙酰辅酶A (CoA)，限制了TCA循环中间体并改善了HSC的活化。在小鼠中，HSC特异性PCK1的丢失加速了饮食诱导的肝纤维化。值得注意的是，造血干细胞中缺乏PCK1的小鼠在正常饮食下也会发生自发性纤维化。这些发现表明，PCK1缺失导致的断裂性纤维化增强糖酵解，激活HSC，促进肝纤维化。

据介绍，磷酸烯醇丙酮酸羧激酶1 （Phosphoenolpyruvate carboxykinase 1, PCK1）是肝脏能量代谢的关键整合子，但其在肝脏主要纤维化细胞肝星状细胞（HSCs）中的作用尚不清楚。

附：英文原文

Title: Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis

Author: Eva Novoa, Tamara Parracho, Julica Inderhees, Amaia Rodriguez, Cristina Riobello, Jose Iglesias-Moure, Anabel Fernández-Iglesias, Sara Martinez-Martinez, Ana Senra, Samuel Seoane, Marcos Fondevila, Cristina Iglesias, Alba Cabaleiro, Natalia da Silva Lima, Valentina Dorta, Borja López-Picallo, Lucia Ramos-Lage, Ashwin Woodhoo, Miguel Fidalgo, Maria L. Martínez-Chantar, Francisco Javier Cubero, Miguel López, Carlos Dieguez, Diana Guallar, Vincent Prevot, Robert Schwabe, Gema Frühbeck, Javier Crespo, Marta Varela-Rey, Maria J. Gonzalez-Rellan, Jordi Gracia-Sancho, Paula Iruzubieta, Markus Schwaninger, Ruben Nogueiras

Issue&Volume: 2026-02-23

Abstract: Phosphoenolpyruvate carboxykinase 1 (PCK1) is a key integrator of hepatic energy metabolism, but its role in hepatic stellate cells (HSCs), the main fibrogenic cells in the liver, remains unknown. We found that PCK1 is reduced in HSCs from fibrotic animals and people with fibrosis, correlating negatively with fibrosis severity. Silencing PCK1 activates human HSCs and increases fibrotic markers, whereas ectopic PCK1 expression blunts transforming growth factor β1 (TGF-β1)-induced activation. Activated HSCs show elevated glycolysis and tricarboxylic acid (TCA) cycle activity, but PCK1 overexpression reduces acetyl-coenzyme A (CoA), limiting TCA cycle intermediates and ameliorating HSC activation. In mice, HSC-specific PCK1 loss accelerates diet-induced liver fibrosis. Notably, mice lacking PCK1 in HSCs also develop spontaneous fibrosis on a normal diet. These findings show that disrupted cataplerosis from PCK1 loss enhances glycolysis and activates HSCs, promoting liver fibrosis.

DOI: 10.1016/j.cmet.2026.01.016

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(26)00016-1