Monocyte OR6A2 Promotes Cardiac Ischemia‑Reperfusion Injury via NR4A1/p53‑Driven Mitochondrial Dyshomeostasis and IL‑1α–Mediated Endothelial Adhesion

Here, we report that the olfactory receptor OR6A2, activated by octanal, promotes mitochondrial fission while suppressing mitophagy via the NR4A1/p53 axis in monocytes under hypoxia/reoxygenation stress. This uncoupling generates sustained mitochondrial reactive oxygen species (mtROS), licensing surface pro-IL-1α expression, which engages endothelial IL-1R1 to drive monocyte-endothelial adhesion, microvascular injury, and cardiac dysfunction.

Single-cell transcriptomics of IR hearts revealed that Or6a2 deletion enriched autophagy/p53 pathways in monocytes and suppressed monocyte-endothelial communication. Myeloid-restricted Or6a2 silencing or systemic IL-1R1 neutralization preserved microvascular integrity and protected against left ventricular dysfunction in vivo. Our findings define the OR6A2/NR4A1/p53/pro-IL-1α/IL-1R1 axis as a therapeutically tractable pathway in myocardial IR injury.