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Protein post-translational modifications (PTMs) are at the heart status of cellular signaling events and broadly involved in tumor progression. CD147 is a tumor biomarker with various PTMs, promoting tumor metastasis and metabolism reprogramming. Nevertheless, the relationship between the PTMs of CD147 and apoptosis has not been reported. In our study, we produced a specific anti-CD147-K71 di-methylation (CD147-K71me2) antibody by immunizing with a di-methylated peptide and observed that the level of CD147-K71me2 in non-small cell lung cancer (NSCLC) tissues were lower than that in NSCLC adjacent tissues. SETDB1 was identified as the methyltransferase catalyzing CD147 to generate CD147-K71me2. RNA-seq showed that FOSB was the most significant differentially expressed gene (DEG) between wild-type CD147 (CD147-WT) and K71-mutant CD147 (CD147-K71R) groups. Subsequently, we found that CD147-K71me2 promoted the expression of FOSB by enhancing the phosphorylation of p38, leading to tumor cell apoptosis. In vivo experiments showed that CD147-K71me2 significantly inhibited tumor progression by promoting cell apoptosis. Taken together, our findings indicate the inhibitory role of CD147-K71me2 in tumor progression from the perspective of post-translational modification, which is distinct from the pro-cancer function of CD147 itself, broadening our perspective on tumor-associated antigen CD147.