This study reveals that POP1 promotes proliferation in triple-negative breast cancer (TNBC) by m6A-dependent degradation of CDKN1A mRNA. POP1 is significantly up-regulated in TNBC and associated with poor prognosis. Mechanistically, POP1 directly binds to the coding sequence (CDS) region of CDKN1A mRNA and degrades it. This degradation process depends on the N6-methyladenosine (m6A) modification at the 497th site of CDKN1A and the recognition of this modification by YTHDF2. The m6A inhibitor STM2457 potently impaired the proliferation of POP1-overexpressed TNBC cells and improved the sensitivity to paclitaxel. These findings suggest that POP1 plays a pivotal role in promoting TNBC proliferation by degrading CDKN1A mRNA and that inhibition of m6A with STM2457 is a promising therapeutic strategy for TNBC. The study also highlights the clinical significance of POP1 and CDKN1A in TNBC chemotherapy response and prognosis. The results indicate that POP1 regulates CDKN1A degradation, providing potential markers for predicting TNBC chemotherapy response and prognosis, and a potential strategy for sensitizing chemotherapy. The study further confirms that YTHDF2 is the m6A reader mediating CDKN1A degradation. The findings suggest that targeting the m6A pathway could be a promising approach for treating TNBC.This study reveals that POP1 promotes proliferation in triple-negative breast cancer (TNBC) by m6A-dependent degradation of CDKN1A mRNA. POP1 is significantly up-regulated in TNBC and associated with poor prognosis. Mechanistically, POP1 directly binds to the coding sequence (CDS) region of CDKN1A mRNA and degrades it. This degradation process depends on the N6-methyladenosine (m6A) modification at the 497th site of CDKN1A and the recognition of this modification by YTHDF2. The m6A inhibitor STM2457 potently impaired the proliferation of POP1-overexpressed TNBC cells and improved the sensitivity to paclitaxel. These findings suggest that POP1 plays a pivotal role in promoting TNBC proliferation by degrading CDKN1A mRNA and that inhibition of m6A with STM2457 is a promising therapeutic strategy for TNBC. The study also highlights the clinical significance of POP1 and CDKN1A in TNBC chemotherapy response and prognosis. The results indicate that POP1 regulates CDKN1A degradation, providing potential markers for predicting TNBC chemotherapy response and prognosis, and a potential strategy for sensitizing chemotherapy. The study further confirms that YTHDF2 is the m6A reader mediating CDKN1A degradation. The findings suggest that targeting the m6A pathway could be a promising approach for treating TNBC.