Heart transplantation is the most effective strategy for treating end-stage heart failure. However, the shortage of available donor hearts is an increasingly prominent issue. Due to the low survival rates of aged donor hearts, those older than 45 years are generally not recommended for transplantation. It is essential to protect donor hearts from ischemia and hypoxia by using cold storage. Dysfunction of factors that respond to hypothermia may impair the protective mechanisms of aged donor hearts in cold storage, resulting in myocardial damage during transplantation.

Cold inducible RNA-binding protein (CIRBP), a nuclear protein highly homologous across mammals, was initially identified in studies of cold stress response. As one of the cold-shock proteins (CSPs), CIRBP can be rapidly induced under cellular stress conditions, such as hypothermia, hypoxia, and ultraviolet radiation, to stabilize target mRNAs. It regulates their translation by selectively binding to the untranslated region at the 3' end of the transcripts, thereby promoting cellular responses to various extracellular stresses. Studies have demonstrated that CIRBP increases the concentration of ubiquinone (CoQ10) in the heart through the cardiac ubiquinone biosynthesis pathway, thereby resisting the attenuation of hypothermic cardioprotection caused by chronic hypoxia during cardiopulmonary bypass [1]. Another study indicated that while CIRBP is abundant in the brain of infants, its expression level decreases with age [2]. Ferroptosis, a regulatory cell necrosis caused by lipid peroxidation induced by free iron and reactive oxygen species, may also be influenced by CIRBP in relation to the NAD(P)H/FSP1/CoQ10, one of the ferroptosis defense systems. Thus, CIRBP may play a role in myocardial damage induced by ferroptosis, which could contribute to the failure of aged donor hearts in maintaining hypothermia protection during heart transplantation.

A recent study by Zhu et al., published in the Journal of Clinical Investigation, entitled “Cirbp suppression compromises DHODH-mediated ferroptosis defense and attenuates hypothermic cardioprotection in an aged donor transplantation model” discovered that inhibiting Cirbp in aged hearts reduced the dihydroorotate dehydrogenase (DHODH) mediated ferroptosis defense, thereby weakening hypothermic cardioprotection and exacerbating the ferroptosis in transplantation [3].

To confirm the hypothermic cardioprotection of aged donor hearts, hearts from 10-week-old (young) and 1-year-old (aged) rats were transplanted into young rats after cold storage (6 h). The heart function of aged donor hearts was significantly reduced after transplantation. Moreover, with the treatment of liproxstatin-1 (a ferroptosis inhibitor) during cold storage, it was observed that the primary form of injury in aged donor hearts post-transplantation was ferroptosis, induced by the impairment of hypothermic cardioprotection during cold storage. The study further investigated the mechanisms linking aging to the impairment of hypothermic cardioprotection. The results demonstrated that the expression of CIRBP is inhibited by the decreasing of its transcriptional factor SP1 and the inhibited translocation of Cirbp from nucleus to cytoplasm in aged donor hearts, suggesting that Cirbp is a crucial regulator in the impairment of hypothermic cardioprotection in these hearts. Further examinations revealed that Cirbp deficiency attenuates hypothermic cardioprotection in young donor hearts during cold storage in vivo and exacerbates ferroptosis in cardiomyocytes induced by a cold ischemia model in vitro. Conversely, Cirbp overexpression improves hypothermic cardioprotection in aged donor hearts during cold storage. Mechanistically, CIRBP was proved to bind to Dhodh mRNA, promoting its translation and subsequently increasing the concentration of CoQH2 in hearts, which inhibits ferroptosis induced by the impairment of hypothermic cardioprotection during cold storage. Lastly, treatment with a Cirbp agonist (Zr17-2) during cold storage was shown to enhance hypothermic cardioprotection in aged donor hearts.

In summary, the suppression of Cirbp expression by SP1 in aged donor hearts leads to the inhibition of Dhodh mRNA translation and a decline in CoQH2 proportion. Thus, the hypothermic cardioprotection in aged donor hearts during cold storage is attenuated, resulting in increased ferroptosis levels. The use of a ferroptosis inhibitor (liproxstatin-1) and a Cirbp agonist (Zr17-2) improves hypothermic cardioprotection in aged donor hearts, offering a promising strategy to protect cardiac function in transplantation and increase the survival rate of patients post-transplantation. This study has significant clinical implications for enhancing the efficacy of aged donor hearts in transplantation and expanding the selection criteria for donor hearts.