Work

Itaconate as a central node in immunometabolism and inflammatory control

Year: 2026

Type: article

Abstract: Mitochondria serve as central regulators of cellular bioenergetics and inflammatory signaling, integrating metabolic status with immune responses. Disruption of mitochondrial homeostasis, including altered tricarboxylic acid cycle dynamics, redox imbalance, and aberrant reactive oxygen species production, contributes to persistent inflammation and disease pathogenesis. Among emerging mitochondrial immunometabolic regulators, the IRG1/ACOD1-derived metabolite itaconate has gained attention as a critical molecular integrator linking mitochondrial metabolism to inflammatory control. This review systematically summarizes the biosynthesis of itaconate and its role in mitochondrial metabolic remodeling during inflammation. Itaconate reshapes the tricarboxylic acid cycle and inhibits succinate dehydrogenase, thereby limiting mitochondrial reactive oxygen species generation and preventing amplification of pro-inflammatory signaling. Through covalent modification of KEAP1, it activates the NRF2 antioxidant program, while concurrently restraining NLRP3 inflammasome activation, establishing a mitochondrial metabolic checkpoint that constrains excessive immune activation. Beyond acute metabolic regulation, itaconate coordinates sustained immunoregulatory programs via the ATF3–IκBζ transcriptional axis, autophagy–lysosome system modulation, and epigenetic reprogramming. We further integrate cell-type–specific effects of itaconate across macrophages, dendritic cells, T cells, and neutrophils, and discuss how mitochondrial immunometabolic dysregulation contributes to chronic inflammatory and metabolic disorders. By positioning the IRG1–itaconate axis within the broader framework of mitochondrial immunometabolism, this review highlights mitochondria as a central hub linking metabolic remodeling with inflammatory regulation. Targeting mitochondrial metabolic checkpoints such as the itaconate pathway may provide promising therapeutic strategies for restoring immune homeostasis and treating inflammation-associated diseases.

Source: Journal of Inflammation

DOI: 10.1186/s12950-026-00510-z

Authors: Jingjing Lin, Gang Wang, Fuming Zi

Institutions: Nanchang University, Second Affiliated Hospital of Nanchang University, Zhejiang Shuren University

Language: English

Topic: Immune cells in cancer

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,190