Transcriptomic Profiling of L-Proline Induced Ferroptosis Reveals PPAR?-Mediated Regulatory Networks in HFpEF Progression
This study investigates the molecular mechanisms by which L-proline contributes to diabetic heart failure with preserved ejection fraction (HFpEF) through the induction of ferroptotic stress under metabolic conditions. We found that L-proline exacerbates ferroptosis-related oxidative and lipid peroxidation stress in cardiac tissue within a metabolically driven HFpEF context. Mechanistically, L-proline markedly suppressed PPAR? signaling, a key regulator of lipid metabolism, redox homeostasis, and ferroptosis resistance. Downregulation of PPAR? was accompanied by upregulation of pro-ferroptotic mediators, including ACSL4 and TFR1, indicating enhanced iron-dependent lipid peroxidation and ferroptotic susceptibility. These findings support a mechanistic link between amino acid metabolic remodeling and fibroblast-centered cardiac vulnerability in diabetic HFpEF, highlighting the role of the proline–PPAR?–ferroptosis axis in promoting myocardial fibrosis and diastolic dysfunction under chronic metabolic stress. Overall design: A metabolically driven HFpEF model was established in mice through high-fat diet–associated metabolic stress. Animals were randomly assigned to Control and L-proline–treated groups. Following the experimental intervention period, left ventricular tissues were collected for total RNA extraction and transcriptomic profiling. RNA sequencing was performed on the Illumina NovaSeq 6000 platform to identify differentially expressed genes related to L-proline–associated ferroptotic signaling and PPAR? pathway modulation. Subsequent bioinformatic analyses included differential expression analysis, pathway enrichment analysis, and functional annotation to delineate molecular signatures underlying proline-mediated metabolic remodeling and ferroptosis in HFpEF.