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Notoginsenoside R1 (NGR1) is a neoteric phytoestrogen extracted from Panax notoginseng, and possesses comprehensive pharmacological functions in multitudinous ailments. But, whether NGR1 is utilized in neonatal pneumonia is not clear. This research study aspired to disclose the protective activity of NGR1 in neonatal pneumonia. WI-38 cells were co-stimulated with NGR1 and lipopolysaccharide (LPS, 10 ng/mL), CCK-8 and flow cytometry assays were implemented for cell viability and apoptosis assessment. Real-time quantitative plymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis were executed for inflammatory cytokine determination. MicroRNA-181a (miR-181a) expression was evaluated through RT-qPCR, simultaneously, the impact of miR-181a was estimated in NGR1 and LPS co-managed cells. Dual luciferase report assay was performed to disclose the relation between miR-181a and Toll-like receptor 4 (TLR4). The nuclear factor-κB (NF-κB) and TAK1/JNK pathways were ultimately appraised.We found that NGR1 decreased cell viability, evoked apoptosis and impeded interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) expression and secretions in LPS-managed WI-38 cells. MiR-181a expression was enhanced by NGR1, and miR-181a inhibition inverted the impacts of NGR1 in LPSmanaged WI-38 cells. Besides, TLR4 was predicted to be a firsthand direct target of miR-181a. Furthermore, NGR1 hindered NF-κB and TAK1/JNK pathways through modulating TLR4. These discoveries disclosed the fact that NGR1 protected WI-38 cells against LPS-triggered injury via adjusting the miR-181a/ TLR4 and NF-κB and TAK1/JNK pathways. K E Y W O R D SmicroRNA-181a, neonatal pneumonia, NF-κB, notoginsenoside R1, TAK1/JNK, toll-like receptor 4 | INTRODUCTIONNeonatal pneumonia is a universal ailment among newborns, and is also a major reason for neonatal death. 1 Statistical evidence displays that about 156 million new events of neonatal pneumonia take place around the world each year, and 95% of neonatal pneumonia episodes happen in the developing countries. 2 The clinical manifestations of neonatal pneumonia comprise fever, cough, dyspnea, heart failure, sepsis, and even death. 3,4 The causes of neonatal pneumonia are multitudinous and are linked to malnutrition, unsafe sanitation,