Targeted Hepatic Methylation-Controlled J Protein Inhibition Mitigates Postsurgical Liver Injury and Neuroinflammation in Aged Mice.

BACKGROUND

Advanced age significantly increases postoperative complication risk, including neurological dysfunction. While the liver plays a critical role in surgical recovery, age-related changes in hepatic function remain inadequately studied in perioperative risk assessment. Methylation-Controlled J protein (MCJ), an endogenous negative regulator of mitochondrial function, represents a promising therapeutic target due to its role in exacerbating oxidative stress and compromising metabolic resilience in aging.

METHODS

Young (4-5 months) and aged (24 months), male and female C57BL/6J mice underwent 60-minute laparotomy surgery or a sham procedure. Treatment groups received hepatocyte-targeted GalNAc-siMCJ (10 mg/kg, subcutaneous) 72 hours before surgery based on established knockdown kinetics. Subclinical liver injury (plasma/tissue cytokeratin-18 and microRNA-122), metabolic dysfunction (kynurenine pathway metabolites), blood-brain barrier integrity [cerebrospinal fluid/plasma albumin ratio and calcium-binding protein S100B], neuroinflammation [glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 (Iba1)], and cognitive function (open field and novel object recognition) were assessed 48 hours postsurgery.

RESULTS

Despite normal transaminases (alanine aminotransferase <46 IU/L, aspartate aminotransferase <69 IU/L), livers from aged mice exhibited significant subclinical injury after surgery, with elevated cytokeratin-18 and microRNA-122 ( P < 0.05 vs. aged-sham). This resulted in increased hepatic kynurenine and quinolinic acid ( P < 0.05), blood-brain barrier disruption (increased S100B plasma levels and cerebrospinal fluid/plasma albumin ratio), neuroinflammation (elevated Iba1 immunoreactivity in hippocampus), and cognitive impairment. Hepatic MCJ silencing prevented these alterations in aged mice ( P < 0.05 vs. aged vehicle), without affecting young mice beyond reducing inflammatory markers.

CONCLUSIONS

Targeted hepatic MCJ inhibition mitigates subclinical liver injury, dysregulated kynurenine metabolism, and subsequent neuroinflammation in aged mice after surgery. This liver-brain axis modulation represents a potential therapeutic strategy to prevent perioperative neurological complications in vulnerable older surgical patients.