Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

中文翻译：

---

Irisin 通过 SIRT1 介导的 p53 脱乙酰化来抗铁死亡，从而减轻 1 型糖尿病心肌病

糖尿病心肌病 (DCM) 是 1 型糖尿病 (T1DM) 患者的严重并发症，目前仍缺乏足够的治疗。鸢尾素是一种从含有 5 的 III 型纤连蛋白结构域上切割下来的肽，已被证明可以在心脏缺血再灌注损伤中保护心脏功能。鸢尾素是否在 DCM 中发挥心脏保护作用尚不清楚。 T1DM 是通过多次低剂量腹腔注射链脲佐菌素 (STZ) 诱导的。我们目前的研究表明，STZ 诱导的 TIDM 小鼠的心脏和血清中鸢尾素表达/水平较低。腹腔注射补充鸢尾素可改善 DCM 小鼠受损的心功能，这归因于铁死亡的抑制，因为铁死亡的增加与心脏丙二醛 (MDA) 增加、还原型谷胱甘肽 (GSH) 和溶质载体蛋白表达的减少有关家族 7 成员 11 (SLC7A11) 和谷胱甘肽过氧化物酶 4 (GPX4) 被鸢尾素改善。在存在铁死亡诱导剂erastin的情况下，鸢尾素介导的保护作用被阻断。从机制上讲，鸢尾素处理增加了 Sirtuin 1 (SIRT1) 并降低了 p53 K382 乙酰化，从而通过增加其降解来降低 p53 蛋白表达，从而上调 SLC7A11 和 GPX4 表达。因此，鸢尾素介导的 p53 减少可减少铁死亡并保护心肌细胞免受高葡萄糖造成的损伤。这项研究表明，鸢尾素可以通过 SIRT1-p53-SLC7A11/GPX4 通路抑制 T1DM 患者的铁死亡，从而改善心脏功能。鸢尾素可能是治疗 T1DM 诱发的心肌病的一种治疗方法。