Ferroptosis and sepsis-induced myocardial injury: a prospective clinical study

Sepsis-induced myocardial injury (SIMI) is a common and severe complication of sepsis associated with increased mortality, yet its underlying mechanisms are not fully elucidated. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, has been implicated in preclinical models of septic cardiomyopathy. However, clinical evidence in humans remains limited, and the specificity of related biomarkers requires careful interpretation.

This prospective observational study enrolled 180 ICU-admitted sepsis patients (91 with SIMI and 89 without) from January to June 2025. Serum ferroptosis-related biomarkers, including malondialdehyde (MDA), lipid peroxidation (LPO), glutathione (GSH), reactive oxygen species (ROS), and ferrous iron (Fe²⁺), were measured at 24 h post-admission. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curves, and independent predictors were identified via multivariable logistic regression adjusting for clinical confounders.

Compared with the non-SIMI group, SIMI patients showed significantly altered ferroptosis-related markers (all P < 0.001): higher MDA [6.08 (5.38-6.67) vs. 4.47 (3.92-5.30) nmol/mL], LPO, ROS, and Fe²⁺, and lower GSH. ROC analysis demonstrated moderate-to-good diagnostic discrimination for SIMI (AUC 0.746-0.825), with Fe²⁺ showing the highest AUC (0.825), followed by ROS (0.793) and MDA (0.787); these outperformed BNP but were inferior to cTnI. Multivariable logistic regression identified Fe²⁺ (OR = 11.883, P < 0.001) as the only independent ferroptosis-related predictor of SIMI, alongside cTnI and APACHE II score. The full model exhibited excellent discrimination (AUC = 0.989) and good calibration (Hosmer-Lemeshow P = 0.935).

Elevated ferroptosis-related biomarkers reflecting systemic oxidative stress and iron dysregulation are significantly associated with SIMI, with Fe²⁺ emerging as an independent predictor. These biomarkers provide additive diagnostic value beyond traditional cardiac markers but are not specific for ferroptosis as a regulated cell death mechanism and likely represent broader redox imbalance in severe sepsis. These findings support further investigation into iron-targeted and oxidative stress-modulating strategies in septic cardiac dysfunction.