To investigate the mechanism of lncRNA (long chain non coding RNA) Rpph1 activating cytopyrosis through AMP-AMPK(activated protein kinase)/Nrf2(nuclear factor E2 related factor 2) signaling pathway, then to promote podocyte injury in DN(diabetes nephropathy). HGPC(Human glomerular podocytes) were cultured in vitro and randomly divided into control group, model group, lncRNA Rpph1 over-expression group, low-expression group, and empty vector group. HGPC were incubated with 5 mmol/L D-glucose as control group, while the other three groups were incubated with 30 mmol/L D-glucose to establish DN model. Liposome transfection method was used to co-incubate stable plasmids carrying Rpph1 over-expression, low-expression, and empty vector with HGPC. qRT-PCR was used to detect lncRNA Rpph1 expression, Western blot was used to detect p-AMPK/AMPK and Nrf2 proteins, as well as the expression levels of cytopyrosis related proteins including NLRP3 (Nod like receptor thermal domain associated protein 3), caspase-1, and GSDMD-N. MTT assay was used to detect cell survival rate. Flow cytometry was used to detecte apoptosis rate. Compared with control group, the expression level of lncRNA Rpph1 in model group significantly increased (P < 0.05). The expression levels of p-AMPK/AMPK, Nrf2, NLRP3, caspase-1, and GSDMD-N proteins significantly increased in model group (P <0.05). The survival rate of model group cells significantly reduced, while apoptosis rate increased in model group (P < 0.5). Compared with model group and empty vector group, lncRNA Rpph1, p-AMPK/AMPK, Nrf2, NLRP3, caspase-1, and GSDMD-N proteins in lncRNA Rpph1 over-expression group significantly increased, and cell survival rate significantly reduced, apoptosis rate increased (P < 0.05). The expression levels of lncRNA Rpph1, p-AMPK/AMPK, Nrf2, NLRP3, caspase-1, and GSDMD-N proteins significantly decreased in lncRNA Rpph1 low-expression group, and cell survival rate significantly increased, apoptosis rate reduced(P < 0.05). In all, High expression of lncRNA Rpph1 in DN may activate cytopyrosis and promote podocyte injury by AMPK/Nrf2 signaling pathway.