Objective <p>The objective of this research is to evaluate the diagnostic and prognostic significance of lncRNA PAX8-AS1 in sepsis, and explore its function in regulating the inflammatory response at the molecular level.</p> Methods <p>This study included 112 sepsis patients and 100 healthy controls. The levels of PAX8-AS1, miR-34a-5p, and target mRNA were quantified using qRT-PCR. Kaplan-Meier analysis was performed to assess 28-day survival. ROC curves were used to evaluate diagnostic efficacy. ELISA measured inflammatory cytokine concentrations. The targeting relationship between PAX8-AS1 and miR-34a-5p, along with the regulatory effect of miR-34a-5p on HDAC1, was confirmed through bioinformatics prediction, dual luciferase reporter assays, and RNA pull-down experiments.</p> Results <p>PAX8-AS1 expression was significantly higher in sepsis patients, and its expression level positively correlated with the severity of sepsis. PAX8-AS1 demonstrated high diagnostic efficacy for sepsis with an AUC of 0.913. Furthermore, the lower 28-day cumulative survival was observed in patients with high PAX8-AS1 expression relative to their low-expression counterparts. In THP-1 cells, silencing PAX8-AS1 suppressed the inflammatory response triggered by LPS. Mechanistically, PAX8-AS1 sponges miR-34a-5p to exacerbate the inflammatory response. HDAC1 is a direct target of miR-34a-5p.</p> Conclusions <p>PAX8-AS1 is highly expressed in sepsis patients and demonstrates diagnostic and prognostic value. By binding to miR-34a-5p to upregulate HDAC1 expression, it promotes inflammatory response.</p>