PURPOSE: Single nucleotide polymorphisms (SNPs) are commonly found in lncRNA, and can regulate its expression. The study examined the genotype and allele distributions of rs9839776 polymorphism in lncRNA SOX2OT in sepsis patients with acute kidney injury (AKI), as well as its expression changes. The function of SOX2OT in AKI cell model was also elucidated. PATIENTS AND METHODS: Serum SOX2OT levels were examined via qRT-PCR in 450 septic patients including 202 cases with AKI and 248 without. Genotyping of rs9839776 polymorphism was completed via Taqman real-time PCR. HK-2 cells were treated with LPS to mimic AKI, the cell viability, apoptosis and inflammatory response were evaluated after regulating SOX2OT levels. The function and pathways enriched by the downstream target genes were explored via GO and KEGG analysis. RESULTS: Rs9839776 CC genotype carriers were commonly observed in sepsis patients with AKI, and presented reduced levels of SOX2OT. Serum SOX2OT was lowly expressed in AKI patients, which can distinguish AKI patients from sepsis ones. In vitro, SOX2OT alleviated LPS-induced AKI via mediating cell proliferation, apoptosis and inflammatory response, which was reversed by miR-9-5p. GO and KEGG analysis uncovered significant links of miR-9-5p target genes with cytoskeleton in muscle cells, cell adhesion molecules and prolactin signaling pathway. CONCLUSION: The CC genotype of rs9839776 polymorphism in SOX2OT could affect the susceptibility of AKI for sepsis patients, and its-mediated SOX2OT downregulation may serve as a biomarker for AKI. The underlying mechanism might be related to the mediation of the SOX2OT/miR-9-5p axis.