Intestinal fibrosis is a prevalent complication of Crohn's disease (CD), characterized by excessive deposition of extracellular matrix (ECM), and no approved drugs are currently available for its treatment. Sirtuin 4 (SIRT4), a potent anti-fibrosis factor in mitochondria, has an unclear role in intestinal fibrosis. In this study, fibroblasts isolated from biopsies of stenotic ileal mucosa in CD patients were analyzed to identify the most down-regulated protein among SIRT1–7, and SIRT4 was found to be the most affected. Moreover, in vivo and in vitro models of intestinal fibrosis, SIRT4 expression was significantly decreased in a TGF-β dependent manner, and its decrease was negatively associated with disease severity. SIRT4 impeded ECM deposition by inhibiting glutaminolysis, but not glycolysis, and α-ketoglutarate (α-KG) was identified as the key metabolite. Specifically, SIRT4 hinders SIRT5’s stabilizing interaction with glutaminase 1 (GLS1), thereby facilitating the degradation of GLS1. KDM6, rather than KDM4, is a potential mediator for α-KG-induced transcription of ECM components, and SIRT4 enhances the enrichment of H3K27me3 on their promotors and enhancers. These findings indicate that the activation of TGF-β signals decreases the expression of SIRT4 in intestinal fibrosis, and SIRT4 can facilitate GLS1 degradation, thereby resisting glutaminolysis and alleviating intestinal fibrosis, providing a novel therapeutic target for intestinal fibrosis.

肠道纤维化是克罗恩病（CD）的常见并发症，其特征是细胞外基质（ECM）过度沉积，目前尚无批准的药物可用于治疗。Sirtuin 4 (SIRT4) 是线粒体中一种有效的抗纤维化因子，在肠道纤维化中的作用尚不清楚。在这项研究中，对从 CD 患者狭窄回肠粘膜活检中分离出的成纤维细胞进行了分析，以确定 SIRT1-7 中下调最多的蛋白，并且发现 SIRT4 受影响最大。此外，在肠道纤维化的体内和体外模型中，SIRT4表达以TGF-β依赖性方式显着降低，且其降低与疾病严重程度呈负相关。SIRT4 通过抑制谷氨酰胺分解而非糖酵解来阻碍 ECM 沉积，并且 α-酮戊二酸 (α-KG) 被确定为关键代谢物。具体而言，SIRT4 阻碍 SIRT5 与谷氨酰胺酶 1 (GLS1) 的稳定相互作用，从而促进 GLS1 的降解。KDM6（而不是 KDM4）是 α-KG 诱导的 ECM 成分转录的潜在介质，SIRT4 增强了 H3K27me3 在其启动子和增强子上的富集。这些发现表明，TGF-β信号的激活降低了肠纤维化中SIRT4的表达，而SIRT4可以促进GLS1降解，从而抵抗谷氨酰胺分解，减轻肠纤维化，为肠纤维化提供了新的治疗靶点。