2. Academic Validation
  3. Oxytocin ameliorates cardiac hypertrophy by inhibiting mitochondrial dysfunction and pyroptosis via AMPK/PGC-1α /TFAM pathway

Oxytocin ameliorates cardiac hypertrophy by inhibiting mitochondrial dysfunction and pyroptosis via AMPK/PGC-1α /TFAM pathway

  • Life Sci. 2026 Apr 15:391:124281. doi: 10.1016/j.lfs.2026.124281.
Quan Wang 1,  Xi Qian 1,  Yu Zhao 1,  Wen Wu 1,  Jin Liu 1,  Na Fu 1,  Lingyan Wang 1,  Haiyan Qin 1,  Zhuoran Wang 2,  Yuqiao Yang 3,  Jinqiao Qian 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
  • 2 Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. Electronic address: [email protected].
  • 3 Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. Electronic address: [email protected].
  • 4 Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China. Electronic address: [email protected].
PMID: 41722768 DOI: 10.1016/j.lfs.2026.124281
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.

Keywords

AMPK/PGC-1α pathway; Cardiac hypertrophy; Mitochondrial dysfunction; Oxytocin; STING/NLRP3 pathway.

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