Microglial metabolic reprogramming drives cognitive decline in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a rapidly growing public health concern and an emerging contributor to dementia, yet the mechanisms linking cardiometabolic dysfunction to neurodegeneration remain poorly understood. Here, we demonstrate that HFpEF drives a sustained neuroinflammatory state through microglial metabolic reprogramming. Using a clinically relevant murine model of HFpEF, we identified robust induction of HIF-1α signaling in microglia via integrated transcriptomics and metabolomics, coupled with increased glycolytic metabolism revealed by extracellular flux analysis. Conditional deletion of Hif1a in microglia during HFpEF attenuated neuroinflammation, preserved white matter integrity, and rescued cognitive performance. We further identify Sema4D as a HIF-1α–dependent, microglia-derived effector linking metabolic stress to white matter injury. These findings establish a mechanistic bridge between cardiovascular disease and cognitive dysfunction and reveal microglial HIF-1α signaling as a tractable therapeutic strategy for preventing cognitive decline in cardiometabolic disease.