• Authors: Xu B. et al.
  • Year: 2022
  • Journal: Adv Sci 9 e2204697
  • Applications: in vivo / siRNA / in vivo-jetPEI


In Vivo siRNA Delivery: The in vivo-jetPEI (Polyplus Inc.) was used for siRNA delivery according to the manufacturer’s instructions. To address whether kyat2 upregulation was causally linked to liver NAD decline and lipid peroxidation, cationic liposome encapsulated short interfering RNAs (siRNAs) targeting mouse Kyat2 (siKyat2) were injected intravenously into the mice and hepatic IR was performed 48 h later (Figure S5A, Supporting Information). Kyat2 knockdown in the ischemic livers was confirmed by immunoblotting, with >50% decrease in protein expression compared to ctrl siRNA (siCtrl)


Hepatic ischemia-reperfusion (IR) injury remains a common issue lacking effective strategy and validated pharmacological targets. Here, using an unbiased metabolomics screen, this study finds that following murine hepatic IR, liver 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA) decline while kynurenine and kynurenic acid (KYNA) increase. Kynurenine aminotransferases 2, functioning at the key branching point of the kynurenine pathway (KP), is markedly upregulated in hepatocytes during ischemia, shifting the kynurenine metabolic route from 3-HAA and QA to KYNA synthesis. Defects in QA synthesis impair de novo nicotinamide adenine dinucleotide (NAD) biosynthesis, rendering the hepatocytes relying on the salvage pathway for maintenance of NAD and cellular antioxidant defense. Blocking the salvage pathway following IR by the nicotinamide phosphoribosyltransferase inhibitor FK866 exacerbates liver oxidative damage and enhanced IR susceptibility, which can be rescued by the lipid peroxidation inhibitor Liproxstatin-1. Notably, nicotinamide mononucleotide administration once following IR effectively boosts NAD and attenuated IR-induced oxidative stress, inflammation, and cell death in the murine model. Collectively, the findings reveal that metabolic rewiring of the KP partitions it away from NAD synthesis in hepatic IR pathophysiology, and provide proof of concept that NAD augmentation is a promising therapeutic measure for IR-induced liver injury.

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