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OSMAC strategy is a useful tool for discovering series of metabolites from microorganism. Five new sambutoxin derivatives (1 – 2 , 4 , 8 – 9), together with seven known compounds (3 , 5 – 7 , 10 – 12), were isolated from Talaromyces sp. CY-3 under OSMAC strategy and guidance of molecular networking. Their planar structures and absolute configurations were determined by NMR, HRESIMS, ECD spectra and common biosynthetic pathway. In bioassay, compounds 1 – 12 showed cytotoxicity to tumor cell lines with IC 50 values in the range of 1.76–49.13 μM. The antitumor molecular mechanism of 10 was also explored. In vitro compound 10 significantly inhibited the growth and proliferation of two lung cancer cell lines (A549 and H1703). Furthermore, colony formation, EdU analysis, flow cytometry and Western blot analysis showed that 10 could induce cell cycle arrest in G0/G1 phase by promoting the expression of p53 and p21. The molecular mechanism of its antitumor effects in vitro is that 10 arrests the cell cycle by activating the p21/CyclinD1/Rb signaling pathway and the p53 pathway. Our results identified a lead small molecule compound with efficient antitumor growth and proliferation activity. [Display omitted] • Five new 2-hydroxy-4-pyridone derivatives were isolated from Talaromyces sp. CY-3. • Compound 1 represents of the first sambutoxin with 7 R and 11 S configurations. • SARs of sambutoxins on cytotoxicity to tumor cell lines were discussed. • 10 arrests the cell cycle by activating the p21/CycinD1/Rb signaling pathway. [ABSTRACT FROM AUTHOR]