GDF11 protects against sepsis-induced myocardial injury and cardiac dysfunction by targeting the Nrf2 signaling pathway-dependent ferroptosis

Sepsis, a systemic inflammatory response syndrome caused by infection, can lead to life-threatening multi-organ dysfunction. Among its complications, sepsis-induced cardiomyopathy (SIC) represents one of the most severe conditions with poor prognosis. Currently, pharmacological options for clinical management of SIC are limited and often yield suboptimal outcomes, necessitating the urgent exploration of novel therapeutic strategies. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, possesses a variety of biological properties. Importantly, recent studies have highlighted the crucial protective role of GDF11 in various cardiovascular diseases. However, to date, there have been no reports on the alterations and effects of GDF11 in SIC. In this study, we initially observed a significant downregulation of GDF11 expression in both myocardium and serum of C57BL/6 J mice treated with lipopolysaccharide (LPS). Subsequently, through endogenous overexpression of GDF11 or exogenous supplementation with recombinant GDF11, we found that GDF11 mitigated lipid peroxidation-dependent ferroptosis by inhibiting iron accumulation and ameliorating mitochondrial dysfunction, thereby alleviating cardiac dysfunction and myocardial injury in septic mice. Additionally, our cellular experiments demonstrated that GDF11 could also inhibit LPS-induced ferroptosis in neonatal mouse cardiomyocytes. Nevertheless, blocking the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway using ML385 in vivo or Nrf2 siRNA in vitro abrogated the above protective effects of GDF11 against SIC. Taken together, our findings show that GDF11 may alleviate SIC by inhibiting cardiomyocyte ferroptosis through activation of the Nrf2 signaling pathway, suggesting GDF11 as a potential therapeutic target for treating patients with sepsis.