Zhan Xinyu, Bai Yan, Zhu Qing, Gao Yiyun, Li Fan, Bu Qingfa, Zhu Zeyu, Rao Zhuqing, Zhou Haoming
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China.
JHEP Rep. 2025 Jan 22;7(5):101330. doi: 10.1016/j.jhepr.2025.101330. eCollection 2025 May.
BACKGROUND & AIMS: Autophagy plays an important role in liver regeneration. However, most studies are limited to hepatocytes, and the function and mechanism of macrophage autophagy in liver regeneration remain unclear. This study investigated the role of the essential autophagy gene encoding autophagy-related 16-like 1 (), which regulates the macrophage phenotype in liver regeneration.
We generated ( ), knockout (KO) ( ), and myeloid-specific -knock-in ( ) mice. These mice were subjected to 70% partial hepatectomy to demonstrate the role of ATG16L1 in macrophages during liver regeneration.
ATG16L1 expression was significantly upregulated in macrophages during the early stages of liver regeneration. ATG16L1 deletion in macrophages substantially delayed liver regeneration in mice and caused a marked imbalance in Ly6C and Ly6C macrophage proportions in the liver. RNA-sequencing analysis revealed that, compared with macrophages isolated from mice, those from mice exhibited significant downregulation of genes associated with oxidative phosphorylation and upregulation of proinflammatory gene expression. Mechanistically, ATG16L1 loss impaired mitophagy in macrophages, leading to the accumulation of mitochondrial damage and a metabolic shift that promoted proinflammatory macrophage polarization. ATG16L1 deficiency not only promoted macrophage mitochondrial (mt)DNA release and cyclic GMP-AMP synthase-stimulator of interferon genes (STING) activation, but also suppressed STING degradation. Sustained STING hyperactivation and subsequent increased release of downstream interferons further contributed to the inhibition of liver regeneration. Notably, pharmacological activation or genetic overexpression of ATG16L1 significantly enhanced liver regeneration in mice.
ATG16L1 has a pivotal role in liver regeneration by affecting the phenotype and function of macrophages. Thus, targeting ATG16L1 in macrophages could present a novel strategy for promoting liver regeneration.
The autophagy-related gene mediates mitophagy, facilitating the clearance of damaged mitochondria in macrophages following partial hepatectomy and maintaining a reparative macrophage phenotype. ATG16L1 deficiency triggers excessive STING activation and inhibits its degradation, thereby suppressing liver regeneration. Thus, targeting ATG16L1 in macrophages could represent a novel strategy to promote liver regeneration.
自噬在肝脏再生中起重要作用。然而，大多数研究仅限于肝细胞，巨噬细胞自噬在肝脏再生中的功能和机制仍不清楚。本研究调查了编码自噬相关16样蛋白1（ATG16L1）的必需自噬基因的作用，该基因在肝脏再生中调节巨噬细胞表型。
我们构建了ATG16L1野生型（WT）、敲除（KO）和髓系特异性ATG16L1敲入（KI）小鼠。对这些小鼠进行70%部分肝切除术，以证明ATG16L1在肝脏再生过程中巨噬细胞中的作用。
在肝脏再生早期，巨噬细胞中ATG16L1的表达显著上调。巨噬细胞中ATG16L1的缺失显著延迟了小鼠的肝脏再生，并导致肝脏中Ly6C⁺和Ly6C⁻巨噬细胞比例明显失衡。RNA测序分析显示，与从WT小鼠分离的巨噬细胞相比，从KO小鼠分离的巨噬细胞中与氧化磷酸化相关的基因显著下调，促炎基因表达上调。从机制上讲，ATG16L1的缺失损害了巨噬细胞中的线粒体自噬，导致线粒体损伤的积累和促进促炎巨噬细胞极化的代谢转变。ATG16L1缺乏不仅促进巨噬细胞线粒体（mt）DNA释放和环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激物（STING）激活，还抑制STING降解。持续的STING过度激活和随后下游干扰素释放增加进一步导致肝脏再生受到抑制。值得注意的是，ATG16L1的药理激活或基因过表达显著增强了小鼠的肝脏再生。
ATG16L1通过影响巨噬细胞的表型和功能在肝脏再生中起关键作用。因此，针对巨噬细胞中的ATG16L1可能是促进肝脏再生的一种新策略。
自噬相关基因ATG16L1介导线粒体自噬，促进部分肝切除术后巨噬细胞中受损线粒体的清除，并维持修复性巨噬细胞表型。ATG16L1缺乏会引发过度的STING激活并抑制其降解，从而抑制肝脏再生。因此，针对巨噬细胞中的ATG16L1可能是促进肝脏再生的一种新策略。
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