Abstract

Aim Oxytocin (OT) is increasingly recognized as a cardiovascular homeostatic regulator with anti-remodeling potential; however, the mitochondrial and innate immune mechanisms underlying its anti-hypertrophic action remain incompletely defined. We therefore investigated whether OT protects against pathological cardiac hypertrophy by preserving mitochondrial homeostasis and suppressing mitochondria-derived inflammatory signaling. Materials and methods An isoproterenol (ISO)-induced rat model and ISO-stimulated H9c2 cardiomyocytes were used. Cardiac remodeling was assessed by echocardiography, histopathology, and transmission electron microscopy. Hypertrophic/fibrotic markers were quantified by RT-qPCR. Mitochondrial function, oxidative stress, and cytosolic mtDNA leakage were evaluated in vitro. The AMPK/PGC-1α/TFAM axis and the cGAS-STING-NLRP3 inflammasome pathway were interrogated by pharmacological inhibition and gene silencing to establish causality. Key findings OT significantly attenuated ISO-induced cardiac hypertrophy, fibrosis, and inflammatory injury in vivo, accompanied by improved mitochondrial ultrastructure, restored PGC-1α/TFAM signaling, and reduced pyroptosis-related protein expression. In H9c2 cells, OT activated AMPK, rescued PGC-1α/TFAM signaling, alleviated mitochondrial dysfunction and oxidative stress, limited cytosolic mtDNA leakage, and suppressed the cGAS-STING-NLRP3 pyroptosis cascade. Blockade of AMPK or PGC-1α, as well as TFAM knockdown, largely abrogated OT-mediated protection, whereas STING inhibition partially restored the anti-pyroptotic effects under TFAM-deficient conditions. Significance Oxytocin protects against pathological cardiac hypertrophy by preserving mitochondrial integrity and inhibiting oxidative stress– and cGAS–STING–NLRP3 inflammasome-mediated pyroptosis via the AMPK/PGC-1α/TFAM pathway, highlighting its potential as a therapeutic strategy for preventing maladaptive cardiac remodeling.