Background: Sepsis-induced myocardial injury, also known as septic myocardial injury (MI), significantly elevates mortality during life-threatening organ dysfunction. While 2,4-dienoyl-CoA reductase 1 (DECR1), a well-recognized gene signature in septic myocardium and blood, and catalase (CAT), which mitigates cardiac anomalies by suppressing ferroptosis, the interaction between them during septic MI pathogenesis remains unclear. Therefore, this study investigates the underlying mechanism by which DECR1 regulates catalase-mediated ferroptosis to confer cardio-protection.

Methods: We established in vivo septic MI rat models and in vitro human monocytic leukemia cells (THP-1) cell models using 10 mg/kg and 1 μg/mL lipopolysaccharide (LPS), respectively. DECR1 was overexpressed in both systems using lentiviral vectors. Rat serum and peripheral blood mononuclear cells (PBMCs) were isolated for subsequent analyses. Myocardial function was assessed through echocardiography (ejection fraction, fractional shortening). Histopathology (Hematoxylin-Eosin (H&E), Masson's trichrome), oxidative stress markers (MDA, 4-HNE) levels, and ferroptosis-related indicators (PTGS2, ACSL4) were evaluated. Furthermore, the apoptosis rate (Terminal deoxynucleotidyl-transferase-mediated dUTP-nick-end labeling (TUNEL), caspase-3) as well as levels of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6); Enzyme-linked immunosorbent assay (ELISA)) were assessed. Additionally, THP-1 ferroptosis (C11-BODIPY fluorescence), apoptosis levels (annexin V/PI), and antioxidant activities (CAT, superoxidase dismutase (SOD)) were also evaluated.

Results: In septic MI rats, DECR1 expression decreased in PBMCs, while its overexpression attenuated myocardial oxidative stress, accompanied by increased activities/expressions of CAT and SOD, reduced myocardial ferroptosis and histological anomalies, ameliorated cardiac dysfunction, and inhibited serous and myocardial inflammation and myocardial apoptosis (p < 0.05). Furthermore, DECR1 overexpression suppressed ferroptosis, enhanced CAT and SOD activities/expressions, and repressed apoptosis and inflammation in LPS-stimulated THP-1 cells (p < 0.05).

Conclusion: DECR1 deficiency in PBMCs exacerbates septic MI by promoting ferroptosis and inflammation. DECR1 overexpression activates CAT and SOD, thereby suppressing oxidative stress, macrophage ferroptosis, and apoptosis. This study is the first to demonstrate that PBMC-derived DECR1 regulates CAT activity to suppress ferroptosis and mitigate septic MI, offering a novel therapeutic approach for septic MI management.