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Background Recent studies have provided strong evidence that lncRNAs play a functional regulatory role in diabetic retinopathy (DR). The purpose of this study was to investigate the effect of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) in DR. Methods A DR mouse model was established by intraperitoneal injection of streptozotocin (STZ), and then the mouse retinal Müller cells (mMCs) were isolated from retina tissues of mice. Human retinal Müller cell line (HMCs) and mMCs and were treated with high glucose (HG) to simulate an in vitro DR model. XIST expression was detected by qRT-PCR. Next, XIST overexpression was performed in mMCs and HMCs to examine its effect on the activation of Müller cells and production of pro-inflammatory cytokines. Subsequently, the interaction between XIST and SIRT1 was verified, and the ubiquitination level of SIRT1 as well as the stability of SIRT1 protein were assessed. Results XIST was down-regulated in retinal tissues of DR mice and HG-induced HMCs. Overexpression of XIST inhibited HG-induced activation of mMCs and HMCs, and reduced the production of pro-inflammatory cytokines. XIST promoted SIRT1 expression via interacting with SIRT1 and inhibiting the ubiquitination of SIRT1. Furthermore, SIRT1 silencing partly abrogated the effect of XIST overexpression on the activation of mMCs and HMCs as well as the production of pro-inflammatory cytokines induced by HG. Conclusion We concluded that XIST restrained the activation of Müller cells and the production of pro-inflammatory cytokines via stabilizing SIRT1.