Mechanism of HMOX1-associated cardiac ferroptosis in a murine model of SCD. Intravascular hemolysis in SCD causes an increase in circulating heme. Excess non–hemopexin-bound heme enters cardiomyocytes, and HMOX1 is upregulated, resulting in cardiomyocyte Fe²⁺ overload. These events lead to cardiomyocyte ferroptosis, which is responsible for impaired cardiac function. Although both oxidative stress and inflammation due to cardiac iron overload have been shown to cause different types of regulated cell death in cardiomyocytes, detailed knowledge concerning the type of cell death would facilitate vital care, with the potential of improved treatment of SCD.