巨噬细胞利用肝细胞谷氨酸促进肝脏再生，这一成果由生长因子Nabil Djouder研究组经过不懈努力而取得。相关论文于2025年3月26日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组人员报道了一种独特的再生机制，涉及非常规的RPB5前折叠蛋白相互作用因子1 (URI1)，它完全与中央周围肝细胞中的谷氨酰胺合成酶（GS）共定位、结合并激活。遗传性GS或URI1缺失会增加循环谷氨酸水平，加速三分之二肝切除术后的肝脏再生。相反，无主旋律肝细胞URI1过表达阻碍肝脏恢复，这可以通过补充谷氨酸或基因GS消耗来升高谷氨酸来逆转。谷氨酸代谢重编程骨髓源性巨噬细胞，稳定HIF1α，其转录激活WNT3促进YAP1依赖性肝细胞增殖，促进肝脏再生。通过URI1调节GS是一种维持最佳谷氨酸水平的机制，可能是为了根据机体的内稳态和营养供应对肝脏生长进行时空微调。因此，在急性和慢性损伤模型中，包括低谷氨酸水平的肝硬化小鼠和肝切除术后早期死亡小鼠，以及90%肝切除术小鼠，谷氨酸添加可增强肝细胞增殖和存活。

此外，URI1和GS的表达在人肝细胞中共定位，并在肝脏疾病的各个阶段与免疫细胞中的WNT3相关。因此，补充谷氨酸可能支持肝脏再生，有利于等待移植或肝切除术后恢复的患者。

据悉，肝切除术后的肝脏再生遵循与人体特定需求的精确协调。然而，影响其效率的分子机制、因素和特定的肝细胞群仍不清楚。

附：英文原文

Title: Macrophages harness hepatocyte glutamate to boost liver regeneration

Author: Rigual, Mara del Mar, Angulo-Aguado, Mariana, Zagorac, Sladjana, lvarez-Daz, Ruth, Bentez-Mondjar, Marta, Yi, Fengming, Martnez-Garay, Carlos, Santos-de-Frutos, Karla, Kim, Eunjeong, Campos-Olivas, Ramn, Djouder, Nabil

Issue&Volume: 2025-03-26

Abstract: Liver regeneration after hepatectomy follows accurate coordination with the body’s specific requirements1,2,3. However, the molecular mechanisms, factors and particular hepatocyte population influencing its efficiency remain unclear. Here we report on a unique regeneration mechanism involving unconventional RPB5 prefoldin interactor 1 (URI1), which exclusively colocalizes with, binds to and activates glutamine synthase (GS) in pericentral hepatocytes. Genetic GS or URI1 depletion in mouse pericentral hepatocytes increases circulating glutamate levels, accelerating liver regeneration after two-third hepatectomy. Conversely, mouse hepatocytic URI1 overexpression hinders liver restoration, which can be reversed by elevating glutamate through supplementation or genetic GS depletion. Glutamate metabolically reprograms bone-marrow-derived macrophages, stabilizing HIF1α, which transcriptionally activates WNT3 to promote YAP1-dependent hepatocyte proliferation, boosting liver regeneration. GS regulation by URI1 is a mechanism that maintains optimal glutamate levels, probably to spatiotemporally fine-tune liver growth in accordance with the body’s homeostasis and nutrient supply. Accordingly, in acute and chronic injury models, including in cirrhotic mice with low glutamate levels and in early mortality after liver resection, as well as in mice undergoing 90% hepatectomy, glutamate addition enhances hepatocyte proliferation and survival. Furthermore, URI1 and GS expression co-localize in human hepatocytes and correlate with WNT3 in immune cells across liver disease stages. Glutamate supplementation may therefore support liver regeneration, benefiting patients awaiting transplants or recovering from hepatectomy.

DOI: 10.1038/s41586-025-08778-6

Source: https://www.nature.com/articles/s41586-025-08778-6