ROS-responsive diselenide exosomes restore mitophagy to resolve sterile inflammation in liver IRI

Area of Science:

• Hepatology
• Immunology
• Mitochondrial Biology

Background:

• Liver ischemia-reperfusion injury (IRI) is a major cause of graft dysfunction and post-surgical complications.
• Hepatocellular MST1 is upregulated in IRI and impairs mitochondrial clearance via PINK1-dependent mitophagy.
• mtDNA leakage from defective mitochondria activates macrophage cGAS-STING signaling, exacerbating inflammatory injury.

Purpose of the Study:

• To investigate the role of MST1-mediated mitophagy blockade in liver IRI.
• To evaluate the therapeutic potential of curcumin delivered via engineered extracellular vesicles (Curcumin@EV@Se) for liver IRI.

Main Methods:

• Investigated MST1 and PINK1 in IRI models.
• Assessed curcumin's effect on the MST1-PINK1 axis and mitophagy.
• Engineered ROS-responsive, stealth extracellular vesicles (EVs) for curcumin delivery (Curcumin@EV@Se).
• Evaluated Curcumin@EV@Se in oxygen-glucose deprivation/reoxygenation and murine hepatic IRI models.

Main Results:

• MST1 upregulation blocks PINK1-dependent mitophagy, leading to mtDNA leakage and cGAS-STING activation in IRI.
• Curcumin@EV@Se treatment restored mitophagy, preserved mitochondrial potential, and reduced oxidative stress and inflammation.
• In vivo, Curcumin@EV@Se significantly decreased liver necrosis, improved liver function markers, and promoted regeneration.

Conclusions:

• MST1-mediated mitophagy blockade and subsequent cGAS-STING activation represent a key pathogenic mechanism in liver IRI.
• Curcumin@EV@Se is a promising, mechanism-guided therapy that restores mitochondrial quality control and dampens innate immune responses.
• This approach holds translational potential for liver transplantation and acute hepatic injury.