Targeting mitochondrial dynamics emerges as an effective strategy of cardioprotection against trastuzumab-induced mitochondrial functional aberrations and cardiotoxicity in rats

Trastuzumab (Trz) is a targeted anticancer therapy that specifically acts on tumors overexpressing the human epidermal growth factor receptor 2 (HER2) protein. Previous research has shown that Trz can induce cardiotoxicity by altering mitochondrial function. While modulating mitochondrial dynamics with Mdivi-1 and M1 has shown cardioprotective effects in various cardiac conditions, their impact on Trz-induced cardiotoxicity in rats remains unclear. In this study, thirty-two male Wistar rats were divided into a control group (CON, n = 8) and a Trz-treated group (4 mg/kg/day, i.p. for 7 days, n = 24). The Trz group was further randomized into subgroups receiving either: 1) vehicle (VEH, 3 % DMSO, i.p., n = 8), 2) the mitochondrial fission inhibitor Mdivi-1 (MDV, 1.2 mg/kg/day, i.p., n = 8), or 3) the mitochondrial fusion promoter M1 (2 mg/kg/day, i.p., n = 8). All interventions began on the first day of Trz administration and continued for 7 days. At the end, cardiac function was then assessed, and heart tissue was collected for biochemical analysis. Trz-treated rats exhibited cardiotoxicity, including cardiac dysfunction and injury, as well as disrupted mitochondrial and autophagic processes, increased inflammation, oxidative stress, apoptosis, ferroptosis, and pyroptosis. Co-administration of either Mdivi-1 or M1 with Trz alleviated these harmful effects, suggesting that modulating mitochondrial dynamics might offer a novel therapeutic strategy to mitigate Trz-induced cardiotoxicity.