To elucidate whether SPC mitigated rat MI/RI by up-regulating USP22 expression, we silenced USP22 in MI/RI rats with SPC administration and subjected H/R-treated H9c2 cells to SPC treatment, and uncovered that LVEF% and LVFS% were both reduced, myocardial fiber arrangement was disturbed, cardiomyocyte interstitial edema was augmented and inflammatory cell infiltration was enhanced, myocardial infarction area was increased, in conjunction with suppressed H9c2 cell viability, increased apoptosis rate and enhanced the levels of CK-MB, cTnI and serum LDH. This evidence concerns the gene USP22 and myocardial infarction.