Itaconate as the endogenous brake of proinflammatory macrophage activation alleviates inflammation in liver fibrogenesis.
- 1Laboratory for Clinical Medicine, Department of Cell Biology, Capital Medical University, Beijing, China.
Abstract
Background
Liver inflammation and fibrosis are reparative responses to chronic liver injury. Bone marrow-derived monocyte/macrophages (BMDMs) are key participants. Our previous study demonstrated that BMDM can be activated as a proinflammatory phenotype by sphingosine-1-phosphate (S1P). Aconitate decarboxylase 1 (ACOD1)/itaconate is an anti-inflammatory molecule. However, it remains unclear whether ACOD1/itaconate is involved in S1P-induced BMDM activation.Methods
A methionine-choline-deficient and high-fat diet was used to induce liver injury and fibrosis in mice. To clarify the role of endogenous ACOD1/itaconate in BMDMs in liver fibrosis, we established 2 types of chimeric mice: (1) bone marrow (BM) Acod1 deficiency (WT or Acod1 knockout BM was transplanted into wild-type mice) and (2) exclusive BM Acod1 expression (WT or Acod1 knockout BM was transplanted into Acod1 knockout mice).Results
Single-cell RNA sequencing data revealed that Acod1 was highly expressed in injured BMDMs. Acod1+ BMDMs exhibited a proinflammatory phenotype with elevated expression of proinflammatory genes. In vitro, ACOD1 expression and itaconate production were upregulated in S1P-treated BMDMs. Endogenous ACOD1/itaconate in BMDMs suppressed BMDM proinflammatory activation by forming negative feedback with NF-κB signaling. S1P-regulated ACOD1 expression and BMDM activation via the same signaling pathway (S1PR2/MAPK/NF-κB signaling), indicating the endogenous brake function of ACOD1/itaconate. In chimeric mice with BM Acod1 deficiency, the abolition of the endogenous brake function of ACOD1/itaconate aggravated liver inflammation/fibrosis. Exclusive BM Acod1 expression showed the opposite effects.Conclusions
ACOD1/itaconate exerts an endogenous brake function in the proinflammatory activation of BMDMs during chronic liver injury. Our data demonstrate the role of ACOD1/itaconate in S1P-induced BMDM activation, further indicating that ACOD1/itaconate is a potential therapeutic strategy for liver inflammation/fibrosis.
Related
- Remote ischemic conditioning mitigates diesel exhaust-induced pulmonary fibrosis by alleviating pulmonary inflammation and fibrogenesis
- SIK2 antagonizes postinfarction cardiac repair by driving macrophage proinflammatory and impairing efferocytosis
- Maternal nonylphenol exposure induces offspring intestinal injury and enteric neuronal defects involving proinflammatory macrophage polarization
- Chronic Microcystin-LR Exposure Induces Colorectal Inflammation Associated with Macrophage Infiltration and HIF-1α-Related Glycolytic Reprogramming
- Atractylenolide III attenuates age-related vertebral bone loss by suppressing macrophage inflammation and osteoclastogenesis
BibTeX
@article{zhang2026itaconate,
title = {{Itaconate as the endogenous brake of proinflammatory macrophage activation alleviates inflammation in liver fibrogenesis.}},
author = {Kai Zhang and Tong Li and Wenhui Liu and Weiyang Li and Lin Yang and Na Chang and Liying Li},
journal = {Hepatology communications},
year = {2026},
month = oct,
doi = {10.1097/hc9.0000000000001034},
url = {https://europepmc.org/article/MED/42900160},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Itaconate as the endogenous brake of proinflammatory macrophage activation alleviates inflammation in liver fibrogenesis.
AU - Kai Zhang
AU - Tong Li
AU - Wenhui Liu
AU - Weiyang Li
AU - Lin Yang
AU - Na Chang
AU - Liying Li
PY - 2026
DA - 2026/10/19
JO - Hepatology communications
DO - 10.1097/hc9.0000000000001034
UR - https://europepmc.org/article/MED/42900160
AB - Background Liver inflammation and fibrosis are reparative responses to chronic liver injury. Bone marrow-derived monocyte/macrophages (BMDMs) are key participants. Our previous study demonstrated that BMDM can be activated as a proinflammatory phenotype by sphingosine-1-phosphate (S1P). Aconitate decarboxylase 1 (ACOD1)/itaconate is an anti-inflammatory molecule. However, it remains unclear whether ACOD1/itaconate is involved in S1P-induced BMDM activation.Methods A methionine-choline-deficient and high-fat diet was used to induce liver injury and fibrosis in mice. To clarify the role of endogenous ACOD1/itaconate in BMDMs in liver fibrosis, we established 2 types of chimeric mice: (1) bone marrow (BM) Acod1 deficiency (WT or Acod1 knockout BM was transplanted into wild-type mice) and (2) exclusive BM Acod1 expression (WT or Acod1 knockout BM was transplanted into Acod1 knockout mice).Results Single-cell RNA sequencing data revealed that Acod1 was highly expressed in injured BMDMs. Acod1+ BMDMs exhibited a proinflammatory phenotype with elevated expression of proinflammatory genes. In vitro, ACOD1 expression and itaconate production were upregulated in S1P-treated BMDMs. Endogenous ACOD1/itaconate in BMDMs suppressed BMDM proinflammatory activation by forming negative feedback with NF-κB signaling. S1P-regulated ACOD1 expression and BMDM activation via the same signaling pathway (S1PR2/MAPK/NF-κB signaling), indicating the endogenous brake function of ACOD1/itaconate. In chimeric mice with BM Acod1 deficiency, the abolition of the endogenous brake function of ACOD1/itaconate aggravated liver inflammation/fibrosis. Exclusive BM Acod1 expression showed the opposite effects.Conclusions ACOD1/itaconate exerts an endogenous brake function in the proinflammatory activation of BMDMs during chronic liver injury. Our data demonstrate the role of ACOD1/itaconate in S1P-induced BMDM activation, further indicating that ACOD1/itaconate is a potential therapeutic strategy for liver inflammation/fibrosis.
SN - 2471-254X
ER -