In recent years, obesity has become a serious health problem worldwide globally [1]. Obesity can mediate a variety of chronic diseases including non-alcoholic fatty liver disease, insulin resistance, and obesity-related cardiac dysfunction [[2], [3], [4]]. Previous reports have demonstrated that obesity-mediated cardiac dysfunction may have various mechanisms, including oxidative stress, programmed cell death, low-grade inflammation, etc. [[5], [6], [7]]. However, the specific mechanism of obesity-related cardiomyopathy remains obscure. Therefore, it is imperative to develop novel strategies to prevent and treat obesity-related cardiac dysfunction.

High-fat diet is one of the major causes of obesity. Excessive deposition of saturated fatty acids (SFAs) in cardiomyocytes may be a major cause of obesity-mediated myocardial injury [8]. As a major SFA, palmitic acid is associated with myocardial injury [9]. Previous studies have demonstrated that programmed cell death is an important cause of obesity-related cardiomyopathy [10]. Ferroptosis, as a recent research hotspot, is a new type of iron-dependent cell death. Iron death plays a significant role in obesity-related cardiac dysfunction. It has been reported that PA can mediate cardiac myocyte iron death [11]. However, the specific mechanism of PA-induced cardiac myocyte iron death remains obscure.

Despite the advances in modern medicine, effective drugs against obesity remain to be discovered. Studies have demonstrated that tripterine is a potent anti-obesity reagent and can effectively enhance leptin sensitivity [12][12]. Cel, a natural Tripterygium wilfordii herb product, has been utilized to treat inflammatory diseases, such as rheumatoid arthritis [13][13]. Furthermore, many studies have demonstrated that Cel plays an important protective role against tumors, obesity, and inflammation by reducing oxidative stress [[14], [15], [16]]. However, the specific pharmacological action and mechanism of tripterine remains to be studied.

Herein, the current article aims to elucidate the underlying role of Cel in high-fat diet-related cardiac injury. We first report that Cel can alleviate PA-induced ferroptosis in cardiomyocytes by targeting AKT/GSK3β signaling. Our research may offer a novel insight into developing treatment strategies for high-fat diet-related cardiac injury.