Cardiolipin alleviates insulin resistance by ameliorating mitochondrial dysfunction and promoting fatty acid oxidation

Cardiolipin deficiency is closely associated with mitochondrial dysfunction and metabolic disorders, yet whether it directly modulates insulin resistance remains unknown. Here, we examined the effects of cardiolipin supplementation on insulin resistance and the underlying mechanisms using male C57BL/6J mice fed a high-fat diet, male db/db mice, and dexamethasone-induced insulin-resistant HepG2 cells, a well-established model for investigating hepatic insulin signaling. Intragastric administration of cardiolipin at 5 mg/kg lowered blood glucose, reduced weight gain, improved insulin sensitivity, and alleviated hepatic lipid accumulation in mice, along with decreased serum interleukin-6 and low-density lipoprotein cholesterol levels. Cardiolipin reduced the LC3-II/LC3-I ratio and Tom20 expression in both liver tissue and insulin-resistant HepG2 cells, indicative of enhanced mitophagy. In HepG2 cells, it also attenuated mitochondrial fragmentation, improved mitochondrial membrane potential, lowered reactive oxygen species production, and upregulated the expression of CPT1A and ACAD1. These findings demonstrate that cardiolipin mitigates hepatic insulin resistance by enhancing mitophagy and fatty acid oxidation, representing a promising therapeutic approach for insulin resistance-related metabolic disorders.