Rutin attenuates liver fibrosis via the IRG1-itaconate-Nrf2 axis.
Jiang Ningman, Zhang Jiao, Kuang Ge, Liu Guohao, Wan Jingyuan, Wang Bin, Zhao Zizuo
Abstract
OBJECTIVE: Liver fibrosis is a common consequence of chronic liver injury, driven by persistent inflammation, oxidative stress, and excessive extracellular matrix deposition. The natural flavonoid rutin possesses antioxidant and anti-inflammatory properties and has shown hepatoprotective potential; however, its anti-fibrotic mechanism remains incompletely understood. This study aimed to investigate the protective effects of rutin and its underlying molecular mechanism in a carbon tetrachloride (CCl₄)-induced mouse model of liver fibrosis, with a particular focus on the role of immune-responsive gene 1 (IRG1). METHODS: Liver fibrosis was induced in mice by CCl₄ administration. Hepatic injury, collagen deposition, inflammatory activation, and oxidative stress were evaluated using histological, biochemical, molecular, and transcriptomic approaches. The involvement of IRG1 was assessed by employing IRG1-deficient mice. Direct binding between rutin and IRG1 was examined through molecular docking, molecular dynamics simulations, and the cellular thermal shift assay (CETSA). RESULTS: Rutin treatment markedly alleviated CCl₄-induced hepatic injury, fibrotic deposition, inflammatory cytokine production, and reactive oxygen species accumulation. Mechanistically, rutin directly bound to and stabilized IRG1, which was associated with enhanced IRG1 enzymatic activity and increased endogenous itaconate production. This led to activation of Nrf2-mediated antioxidant signaling and suppression of NLRP3 inflammasome activation. Importantly, the protective effects of rutin were largely abolished in IRG1-deficient mice, confirming that IRG1 is essential for rutin-mediated hepatoprotection. CONCLUSION: These findings identify rutin as a potential anti-fibrotic agent that targets the IRG1/itaconate axis to coordinate antioxidant and anti-inflammatory responses during liver fibrosis.
Key Findings
- Rutin treatment alleviates liver fibrosis by reducing hepatic injury, collagen deposition, inflammatory cytokine production, and reactive oxygen species accumulation in a CCl₄-induced mouse model.
- Rutin directly binds to and stabilizes IRG1, enhancing its enzymatic activity and increasing endogenous itaconate production.
- Activation of the IRG1/itaconate axis by rutin leads to Nrf2-mediated antioxidant signaling and suppression of NLRP3 inflammasome activation, with protective effects abolished in IRG1-deficient mice.
Clinical Significance
Rutin may serve as a potential therapeutic agent for liver fibrosis by targeting the IRG1/itaconate/Nrf2 pathway to reduce oxidative stress and inflammation, offering a novel approach to managing chronic liver injury.
Citation
Jiang Ningman, Zhang Jiao, Kuang Geet al.. Rutin attenuates liver fibrosis via the IRG1-itaconate-Nrf2 axis. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 2026-Jun-20.