MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction.

Hyperoxia-induced oxidative stress is a primary cause of neonatal injury.

Neonatal heart shows a particular susceptibility to hyperoxic toxicity, yet mechanisms and effective therapeutic strategies remain limited.

Oxeiptosis is a ROS-specific programmed cell death.

Mitochondrial-derived peptide MOTS-c possesses well-known anti-oxidative effect.

This study investigated the cardio-protective role of MOTS-c in hyperoxia exposed neonatal mice and its mechanism.

Neonatal mice exposed hyperoxia (85% O 2 ) were used to establish the hyperoxic cardiac injury model.

Additionally, the rat cardiomyocyte cell line H9C2 were subjected to hyperoxic conditions as an in vitro model.

Serum MOTS-c content was measured using enzyme-linked immunosorbent assay.

Hematoxylin and eosin staining, Real-time PCR, Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to evaluate the effects of MOTS-c on hyperoxia-induced cardiac insufficiency.

We found that hyperoxia exposure in neonatal mice led to significant cardiac hypertrophy, fibrosis, and dysfunction, concomitant with decreased serum MOTS-c content.

Administration of MOTS-c markedly ameliorated these pathological changes and restored cardiac function.

In vitro and in vivo experiments revealed that hyperoxia triggers oxidative stress and oxeiptosis via activating KEAP1-PGAM5-AIFM1 axis, and MOTS-c inhibited oxeiptosis.

Mechanistically, MOTS-c could potentially interact with KEAP1, thereby maintaining the KEAP1-PGAM5 interaction, and inhibiting the downstream nuclear translocation of AIFM1.

Notably, KEAP1 overexpression abrogated the protective effects of MOTS-c, confirming KEAP1 as a critical target of MOTS-c in hyperoxia-induced cardiac injury.

MOTS-c attenuates hyperoxic cardiac injury by inhibiting KEAP1-mediated oxeiptosis, highlighting its potential as a novel therapeutic agent for neonatal cardiomyopathy..