Targeting BCAA/PPAR-γ Axis with Pioglitazone Reverses Insulin Resistance and Mitigates Post-Cardiac Arrest Injury.

Abstract

Metabolic dysfunction contributes to poor outcomes after cardiac arrest (CA). Conventional intensive glucose control fails to improve neurological recovery, and the underlying mechanism remains unclear. We aimed to explore whether insulin resistance (IR) induced by dysregulated branched-chain amino acid (BCAA) metabolism is the core driver of post-CA brain injury, and to verify the therapeutic potential of pioglitazone targeting this pathway. A retrospective cohort (121 CA patients) and a prospective case-control study (25 CA patients vs. 21 controls) were conducted to analyze metabolic indicators. A rat CA model and an HT22 cell oxygen-glucose deprivation/reperfusion model were established. Assessed outcomes included functional neurological outcome, mortality at 30 days, and inflammatory biomarkers levels. Clinical investigations revealed that CA patients had significantly elevated glucose variability (22.75% vs. 14.55%, P < 0.0001) which correlated with poor prognosis, and elevated homeostasis model assessment of insulin resistance values (4.98 vs. 2.62, P = 0.001). In CA rat model, systemic and cerebral IR developed by 72 hours post-resuscitation. Metabolic analysis uncovered a localized BCAA accumulation in the post-CA hippocampus, driven by branched-chain ketoacid dehydrogenase kinase (BCKDK) upregulation. This BCAA directly paralyzed insulin signaling by suppressing the peroxisome proliferator-activated receptor-γ (PPAR-γ) pathway, thereby exacerbating neuroinflammation and apoptosis. Pharmacological activation of PPAR-γ with the FDA-approved agonist pioglitazone bypassed this metabolic blockade, effectively restoring insulin sensitivity, mitigating neuronal injury, and robustly improving post-CA survival (by 40%, P < 0.05) and neurological function (Neurological Deficit Score: 66.94 vs. 53.78, P < 0.001). Dysregulated BCAA metabolism triggers IR via PPAR-γ suppression after CA, exacerbating ischemic brain injury. Targeting the BCAA/PPAR-γ/IR axis with pioglitazone effectively reverses this pathology, providing a mechanistically grounded and highly translatable therapeutic strategy for post-resuscitation care.