N6-methyladenosine reader IGF2BP2 regulates NIPSNAP1-mediated mitophagy and mitochondrial dynamics to alleviate hepatic ischemia-reperfusion injury.

BACKGROUND

Hepatic ischemia-reperfusion (I/R) injury related to liver transplantation and hepatic resection remains a challenge in clinical practice. Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury. The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.

AIM: To clarify the protective mechanism of NIPSNAP1 against hepatic I/R, with a focus on mitophagy and mitochondrial dynamics, as well as the potential mechanism by which n6-methyladenosine (m6A) modification regulates NIPSNAP1.

METHODS

Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R. HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.

RESULTS

We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) expression in vivo and in vitro. NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics; in contrast, NIPSNAP1 overexpression resulted in the opposite effects. Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1, thereby regulating its mRNA stability.

CONCLUSION

NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis, serving as a novel target of the m6A reader IGF2BP2. Therefore, targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.