Targeting fatty acid metabolism in hepatic macrophages mitigates acetaminophen-induced liver injury and promotes regeneration in mice

Sep 29, 2026

An overdose of acetaminophen (APAP) can trigger severe liver injury and even death, yet the mechanisms behind acetaminophen-induced liver injury (AILI) remain incompletely defined. This study examines how fatty acid metabolism in hepatic macrophages shapes AILI progression. APAP was used to induce acute injury in mice, and lipid and macrophage functional changes were assessed. Mechanistically, HMGB1 from necrotic hepatocytes elevates FASN via PI3K/AKT/SREBP1, enhancing inflammatory factors and macrophage migration.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Introduction

DOI: 10.1097/HC9.0000000000000865 O R IG INAL ART ICL E Targeting fatty acid metabolism in hepatic macrophages mitigates acetaminophen-induced liver injury and promotes regeneration in mice Xiaoyong Jiang 1 | Beng Wu1 | Liuyu Xie2 | Hao Li2 | Chen Chen 1 | Panpan Huang2 | Xiaoyu Chen3 | Qian Zhu 1,4,5 | Hua Wang5,6 | Chaojie Hu2 1School of Pharmaceutic Science, Anhui Medical University, Hefei, China 2Division of Life Science and Medicine, Department of Clinical Laboratory, First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China 3Anhui International Travel Health Care Center, Hefei, China 4Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China 5Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China 6Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China Correspondence Chaojie Hu, Division of Life Science and Medicine, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, University of Science and Technology of China, Lujiang Road, Hefei 230001, China. Email: [hucj2018@ustc.edu.cn](hucj2018@ustc.edu.cn) Hua Wang, Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Jixi Road, 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Meishan Road, Hefei, 230032, China. [Email:](Email: wanghua@ahmu.edu.cn)[ wanghua@ahmu.edu.cn](Email: wanghua@ahmu.edu.cn) Qian Zhu, School of Pharmacy, Anhui Medical University, Meishan Road, Hefei, 230032, China. Email: [zhuqian@ahmu.edu.cn](zhuqian@ahmu.edu.cn) | | Abstract | | | --- | --- | --- | | | Background: An overdose of acetaminophen (APAP) can cause severe liver injury and may even lead to death. However, the mechanisms that underlie APAP-induced liver injury (AILI) are not fully understood. The extensive liver necrosis resulting from APAP overdose aggravates the sterile inflammatory response by activating resident macrophages and recruiting various immune cells. Numerous studies have highlighted the crucial role of lipid metabolism in macrophage function. This study investigated fatty acid metabolism in hepatic macrophages and its impact on the progression of AILI.
Methods: We administered APAP intraperitoneally to C57/B6L mice to induce acute liver injury and studied lipid changes in hepatic macrophages. We treated hepacytes with APAP and collected the conditioned medium to stimulate macrophages. Moreover, we generated a myeloid-specific knockout of Fasn mice to validate the role of de novo lipogenesis in macrophages during AILI.
Results: We stained liver tissue sections with Bodipy493/503 lipid dye and observed elevated lipid levels in hepatic macrophages after AILI. Mechanistically, HMGB1 released from necrotic hepatocytes increases FASN expression by activating the PI3K/AKT/sterol regulatory element-binding protein-1 (SREBP1) signaling pathway in macrophages. The enhanced de novo lipogenesis increased inflammatory factor expression in macrophages and facilitated their migratory ability. Conversely, myeloid-specific knockout of Fasn reduced the inflammatory response of macrophages and inhibited | | | | | | Abbreviations: APAP, acetaminophen; AILI, acetaminophen-induced liver injury; BMDM, bone marrow–derived macrophage; CM, conditioned medium; DNL, de novo lipogenesis; FASN, fatty acid synthase; HMGB1, high-mobility group protein B1; PI3K, phosphatidylinositol 3-kinase; MoM, monocyte-derived macrophage; SREBP1, sterol regulatory element-binding protein-1 . Xiaoyong Jiang, Beng Wu, and Liuyu Xie contributed equally to this work. Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.hepcommjournal.com. -- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- -----

FAQs

How does APAP overdose lead to liver injury in this work?

The study describes APAP producing toxic reactive metabolites that exhaust glutathione, damage mitochondria and DNA, and cause hepatocyte necrosis, which intensifies sterile inflammation through activation and recruitment of immune cells.

What role does fatty acid metabolism in hepatic macrophages play in AILI?

The findings show elevated lipid levels and increased inflammatory signaling in hepatic macrophages after AILI. These changes are linked to enhanced de novo lipogenesis that supports macrophage inflammatory factor expression and migration.

Which molecular pathway connects HMGB1 to macrophage lipogenesis?

HMGB1 released from necrotic hepatocytes increases FASN expression by activating the PI3K/AKT/SREBP1 signaling pathway in macrophages.

Sep 29, 2026

Upload by LangkahRina