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

Immunometabolism provides critical insights into the pathogenesis and treatment of inflammatory diseases. Itaconic acid (ITA), a key immunomodulatory metabolite derived from the tricarboxylic acid cycle, has been extensively characterized in macrophages; however, its direct effects on NK cells and NK cell-mediated liver pathology remain poorly defined.

Using SCENITH and Seahorse analyses, we assessed ITA's impact on NK cell metabolism via multi-omics, and investigated its underlying mechanisms. The therapeutic potential was then evaluated in a mouse model of poly (I:C)-induced liver injury.

We show that ITA reprograms NK cell metabolism to suppress their proliferation and killing capacity, simultaneously suppressing oxidative phosphorylation while inducing a compensatory glycolytic shift. Multi-omics integration revealed that this metabolic shift corresponds with the upregulation of glycolytic gene networks and significant mitochondrial impairment, mechanistically linked to the inhibition of succinate dehydrogenase (SDH) activity and the downregulation of the NRF1/TFAM mitochondrial biogenesis pathway. ITA also damages mitochondria and impairs autophagic activity, resulting in accumulation of dysfunctional mitochondria in NK cells. All these alterations lead to profound suppression of NK cell proliferation and cytotoxic function. Administration of ITA in mice with poly (I:C) -induced liver injury substantially attenuated hepatic damage and suppressed over-inflammation in the liver. This protective effect was associated with inhibited hepatic infiltration and function of both NK and T cells.

Our findings extend the understanding of the immune regulation and metabolic reprogramming of ITA to NK cells, showing that ITA inhibits SDH activity to down-regulate mitochondrial biogenesis through NRF1/TFAM in NK cells with consequent limitation of cytotoxic function, suggesting the further therapeutic potential of ITA application in NK cells-mediated liver pathologies.