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

Area of Science:

• Immunometabolism
• Cellular Metabolism
• NK Cell Biology

Background:

• Immunometabolism is crucial for understanding inflammatory diseases.
• Itaconic acid (ITA) is an immunomodulatory metabolite with known effects in macrophages.
• The impact of ITA 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 the therapeutic potential of ITA in a mouse model of liver injury.

Main Methods:

• SCENITH and Seahorse analyses were used to assess NK cell metabolism.
• Multi-omics approaches were employed to identify underlying mechanisms.
• A mouse model of poly (I:C)-induced liver injury was used to evaluate therapeutic potential.

Main Results:

• ITA suppresses NK cell proliferation and killing capacity by inhibiting oxidative phosphorylation and promoting glycolysis.
• Mitochondrial impairment, including SDH inhibition and NRF1/TFAM pathway downregulation, was observed.
• ITA administration attenuated liver injury and suppressed inflammation in a mouse model, reducing NK and T cell infiltration.

Conclusions:

• ITA inhibits succinate dehydrogenase (SDH) activity, down-regulating mitochondrial biogenesis via the NRF1/TFAM pathway in NK cells.
• This metabolic reprogramming limits NK cell cytotoxic function.
• ITA demonstrates therapeutic potential for NK cell-mediated liver pathologies.