摘要Gastric cancer(GC)is characterized by high morbidity and mortality rates.Chinese agarwood comprises the resin-containing wood of Aquilaria sinensis(Lour.)Gilg.,traditionally utilized for treating asthma,cardiac ischemia,and tumors.However,comprehensive research regard-ing its anti-GC effects and underlying mechanisms remains limited.In this study,Chinese agarwood petroleum ether extract(CAPEE)demonstrated potent cytotoxicity against human GC cells,with half maximal inhibitory concentration(IC50)values for AGS,HGC27,and MGC803 cells of 2.89,2.46,and 2.37 μg·mL-1,respectively,at 48 h.CAPEE significantly in-duced apoptosis in these GC cells,with B-cell lymphoma-2(BCL-2)associated X protein(BAX)/BCL-2 antagonist killer 1(BAK)likely mediating CAPEE-induced apoptosis.Further-more,CAPEE induced G0/G1 phase cell cycle arrest in human GC cells via activation of the deoxyribonucleic acid(DNA)damage-p21-cyclin D1/cyclin-dependent kinase 4(CDK4)sig-naling axis,and increased Fe2+,lipid peroxides and reactive oxygen species(ROS)levels,thereby inducing ferroptosis.Ribonucleic acid(RNA)sequencing,real-time quantitative poly-merase chain reaction(RT-qPCR),and Western blotting analyses revealed CAPEE-mediated upregulation of heme oxygenase-1(HO-1)in human GC cells.RNA interference studies demonstrated that HO-1 knockdown reduced CAPEE sensitivity and inhibited CAPEE-induced ferroptosis in human GC cells.Additionally,CAPEE administration exhibited robust in vivo anti-GC activity without significant toxicity in nude mice while inhibiting tumor cell growth and promoting apoptosis in tumor tissues.These findings indicate that CAPEE suppresses hu-man GC cell growth through upregulation of the DNA damage-p21-cyclin D1/CDK4 signaling axis and HO-1-mediated ferroptosis,suggesting its potential as a candidate drug for GC treat-ment.