<p>The prevalence of obesity is high among patients with acute promyelocytic leukemia (APL) and is associated with an adverse prognosis, primarily due to cardiovascular adverse events. Arsenic trioxide (ATO), a cornerstone drug for APL treatment, is known to induce cardiotoxicity. Our previous research has demonstrated that metallothionein confers effective protection against ATO-induced injury in cardiomyocytes. This study aims to investigate whether obesity exacerbates ATO-induced cardiotoxicity in APL patients and to determine if metallothionein retains its cardioprotective efficacy. Transgenic mice with cardiac-specific overexpression of metallothionein and wild-type (WT) controls were placed on either a high-fat diet (HFD) or a standard normal diet (ND) starting at 4 weeks of age. After 16 weeks, all mice received daily tail vein injections of either ATO or phosphate-buffered saline as a vehicle control for 4 weeks. Following the treatment period, the mice were euthanized, and cardiac tissues were harvested for subsequent protein and histological analysis. The severity of ATO-induced cardiac injury was exacerbated in the context of obesity. Notably, metallothionein alleviated cardiotoxicity induced by obesity and therapeutic doses of ATO through the inhibition of oxygen free radicals to reduce myocardial oxidative stress injury, the death receptor pathway, and endoplasmic reticulum stress pathway to protect cardiomyocytes from apoptosis. In addition, metallothionein also protected the myocardium from inflammatory responses and fibrosis by suppressing the NF-κB inflammatory signalling pathway, subsequently downregulating the expression of downstream inflammatory cytokines, adhesion molecules and chemokines. Obesity exacerbates the ATO-induced cardiotoxicity, and metallothionein provides protective perspectives.</p>