Targeted Hepatic Methylation-Controlled J Protein Inhibition Mitigates Post-Surgical 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 sham procedure. Treatment groups received hepatocyte-targeted GalNAc-siMCJ (10 mg/kg, subcutaneous) 72 hours pre-surgery based on established knockdown kinetics. Subclinical liver injury (plasma/tissue cytokeratin-18 (CK18), microRNA-122 (miR-122)), metabolic dysfunction (kynurenine pathway metabolites), blood-brain barrier integrity (cerebrospinal fluid (CSF)/plasma albumin ratio, calcium-binding protein S100B), neuroinflammation (glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1)), and cognitive function (open field, novel object recognition) were assessed 48 hours post-surgery. Results: Despite normal transaminases (alanine aminotransferase (ALT) <46 IU/L, aspartate aminotransferase (AST) <69 IU/L), livers from aged mice exhibited significant subclinical injury after surgery, with elevated CK18 and miR-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 CSF/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.