Itaconic acid alleviates acute hepatitis by reprogramming NK cell metabolism with mitochondrial dysfunction

Area of Science:

• Immunometabolism
• NK cell biology
• Mitochondrial function

Background:

• Immunometabolism is crucial for understanding inflammatory diseases.
• Itaconic acid (ITA) is an immunomodulatory metabolite with known effects in macrophages.
• Its impact on Natural Killer (NK) cells and liver pathology is not well understood.

Purpose of the Study:

• To investigate the effects of ITA on NK cell metabolism and function.
• To elucidate the molecular mechanisms underlying ITA's impact on NK cells.
• To evaluate ITA's therapeutic potential in a mouse model of liver injury.

Main Methods:

• SCENITH and Seahorse analyses to assess NK cell metabolism.
• Multi-omics integration to identify molecular pathways.
• Mouse model of poly (I:C)-induced liver injury to evaluate therapeutic efficacy.

Main Results:

• ITA suppresses NK cell proliferation and killing capacity by inhibiting oxidative phosphorylation and promoting glycolysis.
• Mechanisms involve inhibition of succinate dehydrogenase (SDH) and the NRF1/TFAM pathway, leading to mitochondrial impairment.
• ITA administration attenuated liver injury and inflammation in mice by inhibiting NK and T cell infiltration and function.

Conclusions:

• ITA reprograms NK cell metabolism, inhibiting mitochondrial biogenesis and cytotoxic function via SDH and NRF1/TFAM pathways.
• These findings highlight ITA's role in regulating NK cell immunity.
• ITA demonstrates therapeutic potential for treating NK cell-mediated liver pathologies.