Abstract / Summary
Abstract Post-myocardial infarction (MI) depression is a prevalent, severe clinical complication, yet the precise molecular mechanism underlying heart–brain pathological heart–brain crosstalk in this disorder remains poorly elucidated. In this study, we established a mouse MI model with distinct depressive susceptibility phenotypes, including MI-susceptible (MI-sus) and MI-resilient (MI-res) mice, to explore the functional role and regulatory mechanism of plasma extracellular vesicle (EV)-carried mitochondrial DNA (mtDNA) in the pathogenesis of post-MI depression. Our results revealed that MI-sus mice exhibited prominent neuronal injury, synaptic structural disruption and functional dysfunction in the prefrontal cortex (PFC). Mechanistically, plasma EVs derived from MI-sus mice were highly enriched with mtDNA; stereotaxic injection of these EVs into the PFC of healthy naive mice successfully recapitulated depressive-like behaviors and PFC pathological damage. At the molecular level, EV-encapsulated mtDNA triggered microglial innate immune response by activating the cGAS-STING signaling pathway, subsequently inducing microglial pyroptosis and secondary neuronal and synaptic damage in the PFC. Microglia-specific knockdown of cGAS or STING in the PFC markedly attenuated depressive-like behaviors and reversed PFC pathological lesions in MI mice. Collectively, our findings identify the plasma EV–mtDNA–cGAS-STING–pyroptosis signaling axis as a core molecular mechanism mediating pathological heart–brain crosstalk after myocardial ischemia, offering a novel and actionable therapeutic target for the clinical prevention and treatment of post-MI depression.