Isofalcarintriol ameliorates gestational diabetes mellitus-induced β-cell dysfunction by targeting MIF to enhance mitophagy

Insulin resistance and pancreatic β-cell dysfunction are closely associated with impaired mitophagy, forming a core pathological mechanism in gestational diabetes mellitus (GDM). This study investigates the role of isofalcarintriol (IFT), a carrot-derived polyacetylene, in regulating mitochondrial function in GDM-related β-cells. Here, we use a high-fat diet-induced C57BL/6 J pregnant mouse model and high-glucose/palmitic acid (HG/PA)-treated MIN6 β-cells; IFT ameliorates hyperglycemia and insulin resistance, promotes β-cell maturation and proliferation, induces mitophagy, and enhances β-cell antioxidant capacity. Mechanistically, IFT promotes the dissociation of macrophage migration inhibitory factor (MIF) from ubiquitin-specific protease 7 (USP7) through its C224 residue, and induces MIF ubiquitination through F50/L59 residues, thereby driving the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and pancreatic injury recovery. A mitophagy inhibitor eliminates the beneficial effects of IFT, while PINK1 knockdown reverses the mitophagy-promoting effect induced by MIF knockdown. This study reveals IFT as a potent antioxidant protecting β-cells against GDM-induced injury through MIF, highlighting its potential value in GDM treatment.