Sepsis is a systematic inflammatory response syndrome (SIRS) provoked by host infection and represents a major cause of the dismal prognosis in ICU patients [1]. Septic cardiomyopathy is a life-threatening condition commonly found in patients with severe sepsis or septic shock. It is characterized by decreased myocardial contractility and increased cardiac risk, resulting in increased morbidity and mortality. Patients with sepsis mainly die from multiple organ dysfunction [2,3], among which sepsis-induced cardiomyopathy (SIC) is one of the predominant manifestations of sepsis. Nearly 40%–50% of septic patients experience symptomatic myocardial dysfunction [4]. Among various etiological cues for the onset and development of septic cardiomyopathy, disturbed mitochondrial homeostasis, an important machinery for the maintenance of mitochondrial biogenesis, mitochondrial dynamics (fission/fusion), and mitochondrial autophagy (a.k.a., mitophagy), appears to play an important contributing role to the overall organismal health [5,6]. Mitochondrial dysfunction can lead to myocardial inflammation and even heart failure [7]. According to emerging findings, mitochondrial aberrations contribute to the development of septic cardiomyopathy (see Figure 1).

Ferroptosis, a type of nonapoptotic programmed cell death featured by iron-dependent lipid peroxidation (LPO) [8], is implicated in various diseases, including cardiovascular diseases, cancer, and neurodegeneration. Recent studies have suggested that mitochondrial homeostasis also plays a role in septic cardiomyopathy, particularly in the context of ferroptosis [9,10]. Despite advances in the understanding of pathogenesis in septic cardiomyopathy, effective treatment options are rather limited. This review aims to explore the intricate relationship among ferroptosis, mitochondrial homeostasis, and the onset of septic cardiomyopathy. We discuss the current understanding of mitochondrial homeostasis, mitochondrial membrane protein, mitochondrial iron, and mitochondrial antioxidant systems involved in ferroptosis regulation, specifically within the context of septic cardiomyopathy.