Hypoxia-preconditioned hair follicle mesenchymal stem cell-derived exosomes alleviate metabolic dysfunction-associated steatotic liver disease by facilitating mitophagy through the inhibition of the MEK/ERK signaling pathway

Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by its intricate pathogenesis, is strongly linked to metabolic disorders but currently lacks effective therapeutic strategies. Hair follicle mesenchymal stem cell (HF-MSC)-derived exosomes (Exos) have shown significant efficacy in treating multiple diseases, with hypoxia-preconditioned Exos (Hy-Exos) exerting stronger effects. However, the therapeutic potential of Hy-Exos in MASLD remains unclear. Experimental MASLD models were established through free fatty acid (FFA) stimulation of AML12 cells and high-fat diet treatment in mice. The therapeutic effects of Exos and Hy-Exos were evaluated in cellular and mouse models, and miRNA sequencing was conducted to identify the differences between them. Bioinformatics analysis was used to identify the target genes and related pathways of the miRNAs, which were subsequently verified. Mitochondrial dynamics, mitochondrial function and mitophagy were analyzed through integrated immunofluorescence staining and western blotting. Compared with Exos, Hy-Exos demonstrated an improved efficacy in both the FFA-induced AML12 cells and the high-fat diet-induced MASLD mice. Mechanistically, Hy-Exos exerted their therapeutic effects by inhibiting CDH11 through miR-205-5p to suppress the MEK/ERK signaling pathway, which in turn maintained mitochondrial dynamic stability, restored mitochondrial function and enhanced mitophagy. This study revealed that Hy-Exos inhibited MASLD progression and that CDH11, the target gene of miR-205-5p, may be a major target through which Hy-Exos alleviate MASLD.