Xu Dengqiu, Zhang Zehua, Zhu Ziqi, Wei Wenjing, Bai Yipeng, Wang Wen, Zhu Yong, Alimujiang Abudureyimu, Shi Yuze, Zhang Zhen, Li Zhijian, Wu Pengkai, Sun Beicheng
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230001, China; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China; Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Hefei, Anhui, 230001, China; School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230001, China; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China; Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Hefei, Anhui, 230001, China.
J Hepatol. 2025 Aug 8. doi: 10.1016/j.jhep.2025.07.013.
BACKGROUND & AIMS: Identifying the metabolic targets driving liver fibrosis in metabolic-dysfunction-associated steatohepatitis (MASH) is essential for developing effective preventive therapies. However, the metabolic pathways dysregulated in MASH and the underlying molecular mechanisms remain poorly understood. Lon peptidase 1 (LONP1), a mitochondrial protease, is known for its pivotal role in maintaining mitochondrial protein quality surveillance and performing highly regulated proteolytic reactions. This study aims to explore the precise mechanisms by which LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring in liver fibrosis.
We used murine liver fibrosis models, a hepatocyte-specific Lonp1 knockout mouse model, and liver biopsies from patients with MASH. Transcriptomics, proteomics and metabolomics were used to identify the potential metabolites that promote MASH-induced liver fibrosis.
LONP1 expression was reduced in patients and mice with MASH. Hepatocyte-specific LONP1 deficiency results in dihydroorotate dehydrogenase (DHODH) accumulation, elevated orotic acid levels, and aggravated MASH-induced fibrosis. Conversely, the overexpression of LONP1 or the administration of a DHODH inhibitor reduced orotic acid levels and alleviated MASH-induced liver fibrosis in mice. Mechanistically, LONP1 was shown to degrade DHODH selectively in an ATP-dependent manner, thus lowering orotic acid levels and suppressing ATF3 (activating transcription factor 3)-mediated activation of hepatic stellate cells. These findings were validated in patients with MASH, as plasma orotic acid levels correlated negatively with hepatic LONP1 levels and positively with both the expression of fibrotic genes and fibrosis scores.
Our findings demonstrate that the LONP1-DHODH interaction regulates orotic acid metabolism and alleviates MASH-induced liver fibrosis.
Liver fibrosis is one of the main histological determinants of metabolic dysfunction-associated steatohepatitis (MASH), a disease whose incidence has paralleled the worldwide surge in metabolic syndrome. This study reveals that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring via orotic acid metabolism, contributing to the progression of MASH-induced liver fibrosis. These findings suggest that targeting orotic acid or hepatocyte LONP1 may represent a promising therapeutic strategy. Further investigation into mitochondrial orotic acid metabolism may yield novel insights into the pathogenesis of liver fibrosis.
确定驱动代谢功能障碍相关脂肪性肝炎（MASH）肝纤维化的代谢靶点对于开发有效的预防性治疗至关重要。然而，MASH中失调的代谢途径及其潜在的分子机制仍知之甚少。Lon肽酶1（LONP1）是一种线粒体蛋白酶，以其在维持线粒体蛋白质质量监测和进行高度调控的蛋白水解反应中的关键作用而闻名。本研究旨在探讨LONP1将蛋白水解监测与肝纤维化中线粒体代谢重编程联系起来的精确机制。
我们使用了小鼠肝纤维化模型、肝细胞特异性Lonp1基因敲除小鼠模型以及MASH患者的肝活检组织。采用转录组学、蛋白质组学和代谢组学来鉴定促进MASH诱导的肝纤维化的潜在代谢物。
MASH患者和小鼠中LONP1表达降低。肝细胞特异性LONP1缺乏导致二氢乳清酸脱氢酶（DHODH）积累、乳清酸水平升高以及MASH诱导的纤维化加重。相反，LONP1的过表达或给予DHODH抑制剂可降低乳清酸水平并减轻小鼠MASH诱导 的肝纤维化。从机制上讲，LONP1被证明以ATP依赖的方式选择性降解DHODH，从而降低乳清酸水平并抑制激活转录因子3（ATF3）介导的肝星状细胞激活。这些发现 在MASH患者中得到验证，因为血浆乳清酸水平与肝脏LONP1水平呈负相关，与纤维化基因的表达和纤维化评分呈正相关。
我们的研究结果表明，LONP1-DHODH相互作用调节乳清酸代谢并减轻MASH诱导的肝纤维化。
肝纤维化是代谢功能障碍相关脂肪性肝炎（MASH）的主要组织学决定因素之一，MASH的发病率与全球代谢综合征的激增同步。本研究表明，LONP1通过乳清酸代谢将蛋白水解监测与线粒体代谢重编程联系起来，促进MASH诱导的肝纤维化进展。这些发现表明，靶向乳清酸或肝细胞LONP1可能是一种有前途的治疗策略。对线粒体乳清酸代谢的进一步研究可能会为肝纤维化的发病机制带来新的见解。
