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Entinostat, a selective HDAC1/3 inhibitor, has shown anti-tumor activity in small cell lung cancer (SCLC), but the precise molecular mechanisms underlying its efficacy remain incompletely understood. This study aimed to investigate the functional role and mechanism of Entinostat in SCLC, with a focus on HDAC1 inhibition and its downstream effects on cell death pathways. The anti-tumor effects of Entinostat were evaluated in SCLC cell lines and a xenograft mouse model using MTT, flow cytometry, immunofluorescence, western blotting, and rescue experiments with HDAC1 overexpression and pathway-specific inhibitors. We found that Entinostat significantly inhibited SCLC cell viability and induced both apoptosis and autophagy. Mechanistically, Entinostat downregulated HDAC1 protein levels, increased p53 acetylation and phosphorylation, activated AMPK, and suppressed mTOR signaling. HDAC1 overexpression reversed these molecular changes and attenuated Entinostat-induced cytotoxicity. In vivo, Entinostat suppressed tumor growth and consistently modulated the HDAC1/p53/AMPK/mTOR pathway. In conclusion, Entinostat exerts potent anti-tumor activity in SCLC by simultaneously inducing apoptosis and autophagy through epigenetic modulation of p53 via HDAC1 inhibition and subsequent regulation of the AMPK/mTOR axis.