The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. Moreover, a comprehensive summary of the activation strategies of the GSH system is presented, where we mainly identify several promising herbal monomers, which may provide valuable guidelines for the exploration of new therapeutic approaches. Then, we discuss the relationship between the GSH system and ferroptosis in myocardial injury. In this review, we first systematically describe the physiological functions and anabolism of the GSH system, as well as its effects on cardiac injury. Therefore, targeted enhancement of the GSH system along with prevention of ferroptosis in the myocardium is a promising therapeutic strategy.

Moreover, in facing various pathological challenges, the mammalian heart, which possesses high levels of mitochondria and weak antioxidant capacity, is susceptible to oxidant production and oxidative damage.

Meanwhile, a newly proposed type of cell death, ferroptosis, has been demonstrated to be closely related to the GSH system, which affects the process and outcome of myocardial injury. Numerous investigations have suggested that disruption of the GSH system is a critical element in the pathogenesis of myocardial injury. The glutathione (GSH) system is considered to be one of the most powerful endogenous antioxidant systems in the cardiovascular system due to its key contribution to detoxifying xenobiotics and scavenging overreactive oxygen species (ROS).

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