Excessive ROS accumulation contributes to cardiac injury in type 2 diabetes mellitus. Hydrogen sulfide (H₂S) is a vital endogenous gasotransmitter to alleviate cardiac damage in diabetic cardiomyopathy (DCM). However, the underlying mechanisms remain unclear. In this study, we investigated the effects of NaHS administration in db/db mice via intraperitoneal injection for 20 weeks and the treatment of high glucose (HG), palmitate (PA) and NaHS in HL-1 cardiomyocytes for 48 h, respectively. H₂S levels were decreased in hearts of db/db mice and HL-1 cardiomyocytes exposed to HG and PA, which were restored by NaHS. Exogenous H₂S activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4)/glutathione (GSH) pathway, suppressed ferroptosis and mitigated mitochondrial apoptosis in db/db mice. However, these effects were abrogated after Nrf2 knockdown. NaHS treatment elevated the ubiquitination level of Kelch-like ECH-associated protein (Keap1) by preserving its E3 ligase synoviolin (Syvn1), resulting in Nrf2 nuclear translocation. H₂S facilitated the sulfhydration of Syvn1-cys115 site, a post-translational modification. Transfecting Syvn1 C115A in cardiomyocytes exposed to HG and PA partially attenuated the effects of NaHS on Nrf2 and cell death. Our findings suggest that exogenous H₂S regulates Nrf2/GPx4/GSH pathway by promoting the Syvn1-Keap1 interaction to reduce ferroptosis and mitochondrial apoptosis in DCM.

过多的ROS积累会导致2型糖尿病的心脏损伤。硫化氢 (H ₂ S) 是一种重要的内源性气体递质，可减轻糖尿病心肌病 (DCM) 的心脏损伤。然而，其根本机制仍不清楚。在这项研究中，我们通过腹腔注射20周的方式研究了db/db小鼠中NaHS的作用，以及分别用高葡萄糖（HG）、棕榈酸（PA）和NaHS处理HL-1心肌细胞48小时的效果。暴露于HG和PA的db/db小鼠心脏和HL-1心肌细胞中H ₂ S水平降低，而NaHS可恢复这些水平。外源性 H ₂ S 激活 db/db 小鼠的核因子红细胞 2 相关因子 2 (Nrf2)/谷胱甘肽过氧化物酶 4 (GPx4)/谷胱甘肽 (GSH) 通路，抑制铁死亡并减轻线粒体凋亡。然而，这些效应在 Nrf2 敲除后被消除。NaHS 处理通过保留 E3 连接酶滑膜蛋白 (Syvn1) 来提高 Kelch 样 ECH 相关蛋白 (Keap1) 的泛素化水平，从而导致 Nrf2 核易位。H ₂ S 促进 Syvn1-cys115 位点的硫氢化，这是一种翻译后修饰。在暴露于 HG 和 PA 的心肌细胞中转染 Syvn1 C115A 部分减弱了 NaHS 对 Nrf2 和细胞死亡的影响。我们的研究结果表明，外源性 H ₂ S 通过促进 Syvn1-Keap1 相互作用来调节 Nrf2/GPx4/GSH 通路，从而减少 DCM 中的铁死亡和线粒体凋亡。