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ABSTRACT Herein, we examined the protective effect of metoprolol combined with atractylenolide I (Atr I) in acute myocardial infarction (AMI) by regulating the SIRT3 (silent information regulator 3)/β-catenin/peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway. Briefly, 50 rats were randomly divided into the sham operation, model, metoprolol, Atr I, and combination metoprolol with Atr I groups (combined treatment group). The AMI model was established by ligating the left anterior descending coronary artery. After treatment, infarct size, histopathological changes, and cell apoptosis were examined using 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, and the TUNEL assay. The left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), and left ventricular mass index (LVMI) were detected by echocardiography. Endothelin-1 (ET-1), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels were detected using enzyme-linked immunosorbent assays. Furthermore, we measured lactate dehydrogenase (LDH), creatine kinase (CK) isoenzyme (CK-MB), and CK levels. Western blotting was performed to determine the expression of SIRT3, β-catenin, and PPAR-γ. Herein, the combined treatment group exhibited increased levels of LVEF, LVFS, and NO, whereas LVMI, ET-1, TNF-α, IL-6, LDH, CK-MB, and CK levels were decreased. Importantly, the underlying mechanism may afford protection against AMI by increasing the expression levels of SIRT3, β-catenin, and PPAR-γ. Herein (AMI SIRT silent 3/βcatenin/peroxisome 3βcateninperoxisome βcateninperoxisome 3 /β catenin/peroxisome β catenin peroxisome proliferatoractivated proliferator activated PPARγ PPAR γ (PPAR-γ pathway Briefly 5 operation group. . group) artery size changes 2,3,5triphenyltetrazolium 235triphenyltetrazolium triphenyltetrazolium 2,3,5 2 staining hematoxylineosin hematoxylin eosin assay LVEF , (LVEF) LVFS (LVFS) LVMI (LVMI echocardiography Endothelin1 Endothelin 1 Endothelin- ET1, ET1 ET (ET-1) NO (NO) factoralpha factor alpha TNFα, TNFα TNF α (TNF-α) interleukin6 interleukin 6 interleukin- IL6 IL (IL-6 enzymelinked enzyme linked assays Furthermore LDH (LDH) (CK CKMB, CKMB MB (CK-MB) βcatenin, βcatenin catenin, β-catenin PPARγ. γ. PPAR-γ 1, ET-1 α, TNF-α IL6, 6, IL-6 MB, CK-MB decreased Importantly cateninperoxisome 5triphenyltetrazolium 235 2,3, (LVEF (LVFS (ET-1 (NO (TNF-α (IL- (LDH (CK-MB ET- IL- 23 2,3 (ET- (IL 2, (ET