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To explore the effect of tomatidine (TA) on lipopolysaccharide (LPS)-induced nerve cell injury and the underlying mechanism. METHODS: The neuroinflammation model was induced by treating SH-SY5Y cells with LPS. These cells were divided into control (CON), LPS, and LPS+TA groups. The LPS group was treated with 5 μg/mL LPS for 24 h to establish an inflammatory model. The LPS+TA group was first treated with 5 μmol/L tomatidine for 24 h and then co-cultured with 5 μg/mL LPS for 24 h. Cell viability was detected using the CCK-8 assay. RT-qPCR was used to detect the mRNA expression of inflammatory factors tumor necrosis factor-α (TNF-a) and interleukin-1β (IL-βp). The protein expression of transcription factor EB (TFEB), p-TFEB, P62, and microtubule-associated protein 1 light chain 3 (LC3) expression was detected through Western blot. TFEB localization and cleaved caspase-3 expression were detected through immunofluorescence. The cell apoptosis rate was detected through flow cytometry. RESULTS: (1) Compared with the CON group, the LPS group exhibited significant increases in IL-1β and TNF-α mRNA levels (P< 0.05, the cell apoptosis rate, and the p-TFEB level (P<0.01). By contrast, P62, LC3-II/LC3-I, and TFEB protein ex-pression levels decreased significantly (P<0.05), and TFEB was mainly localized in the cytoplasm. (2) Compared with the LPS group, tomatidine treatment significantly decreased the p-TFEB protein expression level (P<0.01), increased the TFEB protein expression level (P<0.01), and promoted the TFEB protein to migrate into the nucleus. After treatment of tomatidine, the LC3-II/LC3-I protein expression level significantly increased (P<0.05),and the cell apoptosis rate significantly decreased (P<0.01). In addition, the TNF-α mRNA level significantly decreased after tomatidine treatment (P< 0.01). CONCLUSION: Tomatidine improves autophagy dysfunction, inflammatory reaction, and cell apoptosis induced by LPS via activating the transcription factor EB. [ABSTRACT FROM AUTHOR]