Objective To explore the effects and underlying mechanisms of microRNA⁃377⁃3p (miR⁃377⁃3p) in hypoxia/reox⁃ygenation (H/R)⁃induced human renal tubule epithelial cells (HK⁃2) injury. Methods To established model of HK⁃2 with H/R,the cells were cultured for 12 h under hypoxic conditions (1%O2, 5%CO2, 94%N2) to induce hypoxic injury. Then, the cells were movedto a normoxic cell incubator (5%CO2, 95%air). MiR⁃377⁃3p inhibitor, mimic, X⁃linked inhibitor of apoptosis (XIAP) targeted small in⁃terfering RNA (si⁃RNA) (si⁃XIAP) and corresponding control vectors were constructed and transfected into HK⁃2 before establishment of the H/R model. According to the random number table method, the HK⁃2 were divided into 7 groups: (5×105 cells per group), normox⁃ic group (NC group), H/R group, miR⁃IC group, miR⁃I group, miR⁃MC group, miR⁃M group, miR⁃XIAP group. The levels ofmiR⁃377⁃3p were detected by reverse transcription polymerase chain reaction (RT⁃PCR) while the cell viability was evaluated with cellcounting kit⁃8 (CCK8). The levels of pro⁃inflammatory cytokines, including interleukin (IL)⁃6 and tumor necrosis factor (TNF)⁃α, were determined by enzyme⁃linked immunosorbent assay (ELISA). The target gene of miR⁃377⁃3p was predicted by bioinformatics softwareand luciferase reporter gene assay was used to detect the effect of miR⁃377⁃3p on luciferase activity in the 3′untranslated region (UTR)of the XIAP messenger RNA (mRNA). CCK8 and ELISA assay were performed to evaluate cell viability and inflammatory factors (IL⁃6 and TNF⁃α) after miR⁃377⁃3p inhibitor+si⁃XIAP+H/R treatment. Results The model of HK⁃2 with H/R was successfully estab⁃lished. Compared with NC group, the levels of miR⁃377⁃3p were upregulated in HK⁃2 with H/R (P<0.05). Compared with H/R group,miR⁃I group significantly suppressed levels of miR⁃377⁃3p, miR⁃M group significantly increased levels of miR⁃377⁃3p (P<0.05). Com⁃pared with NC group, cell viability was decreased, while IL⁃6 and TNF⁃α levels were increased in H/R group (P<0.05). Compared withH/R group, miR⁃I group could enhance cell viability and decrease IL⁃6 and TNF⁃α levels, miR⁃M group inhibited cell viability and in⁃creased the levels of IL⁃6 and TNF⁃α (P<0.05). Bioinformatics software indicated that XIAP was a target gene of miR⁃377⁃3p and lucif⁃erase reporter gene assay revealed that increased expression of miR⁃377⁃3p inhibited luciferase activity of XIAP 3′UTR with the wild⁃type (P<0.05). Furthermore, the results from CCK8 and ELISA assay revealed that XIAP knockdown could reverse the enhance⁃ment of cell viability and downregulation of IL⁃6 and TNF⁃α levels induced by suppression of miR⁃377⁃3p (P<0.05). Conclusions Inhibition of miR⁃377⁃3p could relieve the injury of HK⁃2 caused by H/R possibly through negative regulation of XIAP.