Diabetic peripheral neuropathy (DPN) is a prevalent diabetes mellitus (Feldman et al., 2017) complication and the primary reason for amputation. Meanwhile, long non-coding RNAs (lncRNAs) are a type of regulatory non-coding RNAs (ncRNAs) that broadly participate in DPN development. However, the correlation of lncRNA X-inactive specific transcript (XIST) with DPN remains unclear. In this study, we were interested in the role of XIST in the modulation of DPN progression. Significantly, our data showed that the expression of and sirtuin1 (SIRT1) was inhibited, and the expression of microRNA-30d-5p () was enhanced in the trigeminal sensory neurons of the diabetic mice compared with the normal mice. The levels of LC3II and Beclin-1 were inhibited in the diabetic mice. The treatment of high glucose (HG) reduced the XIST expression in Schwann cells. The apoptosis of Schwann cells was enhanced in the HG-treated cells, but the overexpression of could block the effect in the cells. Moreover, the levels of LC3II and Beclin-1 were reduced in the HG-treated Schwann cells, while the overexpression of was able to reverse this effect. The HG treatment promoted the production of oxidative stress, while the overexpression could attenuate this result in the Schwann cells. Mechanically, was able to sponge and -targeted SIRT1 in the Schwann cells. inhibited autophagy and promoted oxidative stress in the HG-treated Schwann cells, and SIRT1 presented a reversed effect. mimic or SIRT1 depletion could reverse overexpression-mediated apoptosis and autophagy of the Schwann cells. Thus, we concluded that attenuated DPN by inducing autophagy through /SIRT1 axis. XIST and may be applied as the potential targets for DPN therapy.