To explore the potential targets and mechanism of modified Lianpu Decoction in treating Helicobacter pylori(Hp)-positive perioral acne based on network pharmacology and experimental verification.Methods:The effective components，core targets，and signaling pathways of modified Lianpu Decoction in treating Hp-positive perioral acne were obtained by network pharmacology.The mouse model of Hp-positive perioral acne was established by gavage with Hp suspension combined with intracutaneous injection of Propionibacterium acnes.The perioral skin tissue samples of the mice were stained with hematoxylin-eosin(HE)，and serum levels of tumor necrosis factor(TNF-α) and interleukin(IL-6) were determined by enzyme-linked immunosorbent assay(ELISA).The protein levels of nucleotide-binding oligomerization domain 1(NOD1)，Toll-like receptor(TLR4)，and nuclear factor κB(NF-κB) in the perioral skin were determined by Western blotting.Results:A total of 42 key targets of Lianpu Decoction were selected，mainly involving signal transducer and activator of transcription 3(STAT3) and mitogen-activated protein kinase 1(MAPK1).The gene ontology(GO) annotation predicted 477 biological processes.The Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis showed that the key targets were involved in 102 signaling pathways.The animal experiments showed that compared with the blank control group，the modeling elevated the serum levels of TNF-α and IL-6(P<0.01) and up-regulated the expression levels of NOD1，TLR4，and NF-κB in the perioral skin.Compared with the model group，modified Lianpu Decoction and integrated Chinese and Western medicine lowered the serum levels of TNF-α and IL-6(P<0.01) and down-regulated the expression levels of NOD1，TLR4，and NF-κB in the perioral skin(P<0.01).Conclusion:Lianpu Decoction can treat Hp-positive acne in a multi-component，multi-target，and multi-pathway manner by regulating the TLR4/NF-κB signaling pathway.