L-carnitine ameliorates fibrosis and reproductive dysfunction in intrauterine adhesion via restoration of mitochondrial fatty acid oxidation

INTRODUCTION: Intrauterine adhesion (IUA) is a leading cause of secondary infertility, characterized by fibrosis and impaired endometrial regeneration. Although inflammation and fibrotic pathways have been studied, the metabolic mechanisms remain unclear. This study aimed to identify metabolic alterations in intrauterine adhesion and to evaluate whether L-carnitine (LCA) supplementation could restore mitochondrial function and alleviate fibrosis. MATERIAL AND METHODS: Untargeted metabolomic profiling was performed on endometrial tissues from patients with IUA and controls using liquid chromatography-tandem mass spectrometry. An ethanol-induced mouse model of IUA was established and treated with LCA by intraperitoneal injection. Histological, immunohistochemical, and ultrastructural analyses assessed fibrosis, inflammation, and mitochondrial integrity. In vitro, lipopolysaccharide-stimulated endometrial epithelial cells were used to evaluate fatty acid oxidation (FAO), lipid droplet accumulation, mitochondrial function, reactive oxygen species (ROS) production, lipid peroxidation, and transforming growth factor beta secretion after L-carnitine treatment. RESULT: Metabolomics revealed profound depletion of carnitine and derivatives in IUA, accompanied by enrichment of pro-inflammatory prostaglandins and fibrosis-associated metabolites. LCA treatment in mice restored uterine morphology, reduced apoptosis, fibrosis, and inflammation, and improved pregnancy outcomes. In vitro, LCA restored FAO activity, reduced lipid droplet accumulation, preserved mitochondrial membrane potential, suppressed ROS and lipid peroxidation, and decreased TGF-β secretion in LPS-stimulated cells. CONCLUSION: This study establishes carnitine deficiency as a key driver of IUA, demonstrating that it disrupts mitochondrial FAO, promotes oxidative stress, and culminates in fibrosis. LCA supplementation not only restores metabolic homeostasis and reduces fibrotic progression but also improves reproductive outcomes, positioning it as a mechanistically grounded therapy for IUA.