Targeting the FKBP5-ceramide axis driven mitochondrial reprogramming in cardiac macrophages attenuates post-infarct cardiac injury

Plasma ceramide levels are elevated in cardiovascular disease and predict recurrent adverse events and mortality after myocardial infarction (MI). However, mechanisms driving post-MI ceramide accumulation and pharmacologically actionable targets to counteract ceramide-driven myocardial damage are still lacking. Here, we identify FK506-binding protein 5 (FKBP5) as a druggable immunometabolic regulator of ceramide metabolism in cardiac macrophages, linking FKBP5 suppression to interrupted pathological crosstalk among sphingolipid remodeling, mitochondrial impairment and post-MI inflammatory injury. Using murine MI models and FKBP5-deficient cells, we examined FKBP5 inhibition or deficiency reduced infarct size and fibrosis, improved cardiac function, and protected against adverse remodeling. Mechanistically, FKBP5 was associated with the sphingomyelin phosphodiesterase 3 ( Smpd3 ) promoter region and contributed to the regulation of its transcriptional activity after MI, thereby promoting ceramide accumulation. Specifically, FKBP5-mediated ceramide 24:1 (Cer24:1) upregulation impaired mitochondrial redox homeostasis by disrupting electron transport chain integrity, thereby reinforcing M1 polarization and exacerbating myocardial injury. Elevated Cer24:1 directly bound the mitochondrial TU translation elongation factor (TUFM), disrupting electron transport chain integrity and mitochondrial respiration, providing a defined link between ceramide species and mitochondrial dysfunction. Notably, in vivo treatment with Cer24:1 attenuated the cardioprotective effects of FKBP5 inhibition after MI. Collectively, we describe a previously unrecognized FKBP5- Smpd3 -Cer24:1-TUFM signaling axis in cardiac macrophages. FKBP5-governed ceramide metabolism drives macrophage immunometabolic reprogramming, marking FKBP5 as a promising pharmacological target for ischemic heart disease. Our findings support the role of the FKBP5-ceramide axis in mediating post-infarct myocardial dysfunction and highlight pharmacological FKBP5 inhibition as a therapeutic strategy against post-MI cardiac injury.