Aortic dissection (AD) is a life-threatening vascular emergency characterized by vascular smooth muscle cell (VSMC) dysfunction and extracellular matrix degradation. Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine implicated in vascular remodeling, has been suggested to play a role in AD, yet its mechanistic contribution remains unclear. We integrated bulk and single-cell transcriptomic analyses with validation in human and murine AD tissues. Functional roles of MIF were explored using MIF knockout mice, pharmacological inhibition (ISO-1), and adeno-associated virus-mediated overexpression. Mechanistic studies in primary VSMCs examined autophagy flux, AKT/mTOR signaling, and phenotypic switching. Pharmacological modulation with rapamycin and chloroquine was performed to assess autophagy's role. MIF was markedly upregulated in AD tissues, especially in VSMCs. MIF deficiency or ISO-1 treatment significantly reduced AD incidence, rupture, and aortic dilation, while overexpression aggravated disease progression. Mechanistically, MIF suppressed autophagy by activating AKT/mTOR signaling, promoting the synthetic VSMC phenotype. Restoration of autophagy with rapamycin reversed MIF-induced phenotypic switching, whereas chloroquine exacerbated AD. Furthermore, AKT silencing abolished the pathological effects of MIF, and receptor-blocking experiments indicated that CD74 and CXCR2 mediate MIF-driven signaling. MIF is a critical regulator of VSMC phenotypic switching in AD through AKT/mTOR-mediated autophagy suppression. Targeting MIF or enhancing autophagy represents a potential therapeutic strategy for preventing AD progression.
