Non-canonical PPARα Agonism by Arjunolic Acid Mitigates Cardiomyocyte PANoptosis Through a Novel PPARα/CRYAB/IKKα Axis During Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy is manifested by downregulated PPARα driven metabolic dysregulation which culminates into cardiomyocyte apoptosis. Emerging evidences indicate that additional regulated cell death mechanisms also operate during cardiac pathophysiology. Arjunolic acid (AA) has shown antifibrotic effect via tinkering PPARα. The study investigates the underlying noncanonical role of PPARα agonism by AA in amelioration of cardiomyocyte PANoptosis process during pathological hypertrophy. An integrative approach combining in silico, in vitro and in vivo studies using Wistar rat model to uncover the role of AA driven cardio-protection by regression of PANoptosis signaling mechanism via PPARα agonism. AA driven PPARα agonism does not perturb its canonical function of being a transcription factor as it forms a stable structure with RXR. PPARα agonism in hypertrophied cardiomyocytes by AA, drives a molecular rearrangement within cells in two major ways; by interacting with a molecular chaperon CRYAB to repress IKKα mediated activation of pyroptosis and its sequestration of p300 mediated repression of p53 acetylation driven apoptosis in hypertrophied cardiomyocytes. Additionally, repressed activation of NFκB-p65 by PPARα augmentation effectively reduces ROS accumulation that in turn downregulates activation of MLKL driven necroptotic prowess in diseased cardiomyocytes. The present study provides novel mechanistic insights into the existence of PANoptosis during hypertrophic pathophysiology, that drives the diseased cardiomyocytes in unison towards imminent cell death, which could be mitigated by AA driven PPARα agonism leading to improved cardiac function.