Yang Songyuan, Chen Lijia, Din Shikuan, Ye Zehua, Zhou Xiangjun, Cheng Fan, Li Wei
Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Cell Signal. 2025 Jan;125:111479. doi: 10.1016/j.cellsig.2024.111479. Epub 2024 Oct 23.
Cisplatin is extensively utilized in clinical settings for treating solid tumors; However, its use is restricted because of the kidney damage caused by side effects. Moreover, currently, no effective medications have been approved to prevent or treat acute kidney injury induced by cisplatin. Our research indicates that sirtuin 6 (SIRT6) can inhibit ferroptosis induced by cisplatin, and the use of SIRT6 agonists can alleviate acute kidney injury caused by cisplatin.
An animal model of cisplatin-induced acute kidney injury (AKI) was established, followed by RNA sequencing to identify potential differentially expressed genes (DEGs) and associated pathways. To explore the role of SIRT6 in this model, SIRT6 knockout mice were generated, and recombinant adeno-associated virus was employed to achieve SIRT6 overexpression in the mice. In vitro, cells were cultured in a cisplatin-containing medium to establish a cisplatin-induced cell model. The function of SIRT6 was further investigated by overexpressing or knocking down the gene using lentiviral plasmids. To elucidate the underlying molecular mechanisms, we employed RNA sequencing, performed bioinformatics analyses, and conducted chromatin immunoprecipitation assays.
RNA sequencing and Western blot analyses revealed a significant reduction in SIRT6 expression in mice with cisplatin-induced acute kidney injury (AKI). Enhancing SIRT6 expression improved renal function, reduced ferroptosis, and mitigated kidney damage, whereas SIRT6 knockout exacerbated kidney injury and heightened ferroptosis. Mechanistically, RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assays demonstrated that SIRT6 inhibits ferroptosis by reducing the acetylation of histone H4K9ac at the BAP1 promoter. Furthermore, in vitro studies demonstrated that the SIRT6 agonist UBCS039 can alleviate cisplatin-induced acute kidney injury, highlighting its potential therapeutic role in mitigating cisplatin's damaging effects. However, further research is needed to fully elucidate the underlying mechanisms and to validate these findings in vivo.
Our findings underscore the critical role of the SIRT6/BAP1/xCT axis in regulating ferroptosis, particularly via the downregulation of SIRT6, in the context of cisplatin-induced acute kidney injury (AKI). This suggests that SIRT6 could be a promising therapeutic target for treating cisplatin-induced AKI. However, additional research is required to explore the specific mechanisms and fully assess the therapeutic potential of SIRT6 in this context.
顺铂在临床中广泛用于治疗实体瘤；然而，由于其副作用导致的肾损伤，其应用受到限制。此外，目前尚无获批用于预防或治疗顺铂诱导的急性肾损伤的有效药物。我们的研究表明，沉默调节蛋白6（SIRT6）可抑制顺铂诱导的铁死亡，使用SIRT6激动剂可减轻顺铂所致的急性肾损伤。
建立顺铂诱导的急性肾损伤（AKI）动物模型，随后进行RNA测序以鉴定潜在的差异表达基因（DEG）及其相关通路。为探究SIRT6在该模型中的作用，构建了SIRT6基因敲除小鼠，并使用重组腺相关病毒使小鼠体内实现SIRT6过表达。在体外，将细胞培养于含顺铂的培养基中以建立顺铂诱导的细胞模型。通过慢病毒质粒过表达或敲低该基因，进一步研究SIRT6的功能。为阐明潜在的分子机制，我们进行了RNA测序、生物信息学分析及染色质免疫沉淀实验。
RNA测序和蛋白质免疫印迹分析显示，顺铂诱导的急性肾损伤（AKI）小鼠中SIRT6表达显著降低。增强SIRT6表达可改善肾功能、减少铁死亡并减轻肾损伤，而SIRT6基因敲除则加剧肾损伤并加重铁死亡。机制上，RNA测序、生物信息学分析及染色质免疫沉淀实验表明，SIRT6通过减少BAP1启动子处组蛋白H4K9ac的乙酰化来抑制铁死亡。此外，体外研究表明，SIRT6激动剂UBCS039可减轻顺铂诱导的急性肾损伤，凸显了其在减轻顺铂损伤作用方面的潜在治疗作用。然而，需要进一步研究以充分阐明潜在机制并在体内验证这些发现。
我们的研究结果强调了SIRT6/BAP1/xCT轴在顺铂诱导的急性肾损伤（AKI）中调节铁死亡的关键作用，尤其是通过下调SIRT6发挥作用。这表明SIRT6可能是治疗顺铂诱导的AKI的一个有前景的治疗靶点。然而，需要更多研究来探索具体机制并全面评估SIRT6在这种情况下的治疗潜力。
