Objective:　This　study　aimed　to　investigate　the　interaction　and　underlying　mechanisms　between　specificity　protein　1　(Sp1)　and　the　phosphoinositide　3-kinase/protein　kinase　B　(PI3K/AKT)　signaling　pathway　in　the　context　of　doxorubicin-induced　cardiomyopathy　(DIC).　Methods:　A　rat　model　of　DIC　was　established　by　intraperitoneal　injection　of　doxorubicin　(1　mg/kg)　twice　a　week　for　eight　weeks.　Cardiac　function　was　evaluated　using　echocardiography,　and　myocardial　histopathology　was　assessed　by　hematoxylin-eosin　(HE)　staining.　In　vitro,　H9c2　cardiomyocytes　were　treated　with　doxorubicin　(2　mu　mol/L)　to　induce　cardiotoxicity,　followed　by　co-treatment　with　the　Sp1　inhibitor　plicamycin　or　the　PI3K/AKT　inhibitor　LY294002.　Cell　viability　was　measured　by　the　CCK-8　assay.　Oxidative　stress　markers,　including　reactive　oxygen　species　(ROS)　and　lactate　dehydrogenase　(LDH),　were　quantified　using　flow　cytometry　and　colorimetric　assays.　Apoptosis　was　detected　via　TUNEL　staining,　and　protein　expression　of　Sp1,　PI3K,　AKT,　and　Caspase-3　was　analyzed　by　Western　blotting.　Results:　Doxorubicin　treatment　significantly　impaired　cardiac　function　in　rats,　as　evidenced　by　an　increase　in　both　left　ventricular　internal　diameters　during　diastole　(LVIDd)　and　systole　(LVIDs),　along　with　decreased　ejection　fraction　(EF)　and　fractional　shortening　(FS)　(p　＜　0.01).　Myocardial　HE　staining　in　doxorubicin-treated　rats　revealed　disorganized　cardiomyocyte　structures,　edema,　and　cellular　necrosis.　In　vitro,　doxorubicin　exposure　led　to　reduced　H9c2　cell　viability,　elevated　ROS　and　LDH　levels,　and　increased　apoptosis　rates　(p　＜　0.01).　Western　blotting　demonstrated　that　doxorubicin　significantly　downregulated　the　expression　of　Sp1,　PI3K,　and　AKT　while　upregulating　Caspase-3.　Inhibition　of　Sp1　or　PI3K/AKT　exacerbated　these　effects,　resulting　in　further　cardiac　dysfunction,　oxidative　stress,　and　apoptosis.　Moreover,　Sp1　inhibition　led　to　decreased　PI3K/AKT　pathway　activation,　while　PI3K/AKT　inhibition　reciprocally　suppressed　Sp1　expression,　indicating　a　bidirectional　regulatory　relationship.　Conclusion:　Doxorubicin　induces　cardiotoxicity　by　promoting　oxidative　stress　and　apoptosis　through　the　downregulation　of　the　Sp1/PI3K/AKT　signaling　pathway.　Inhibition　of　this　pathway　exacerbates　cardiac　injury,　suggesting　that　targeting　Sp1　and　PI3K/AKT　may　offer　novel　therapeutic　strategies　for　the　prevention　and　treatment　of　DIC.