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Our research reveals a key player in this challenge\u2014POU2F1, a transcription factor known to drive tumor progression. We found this oncogene is markedly overexpressed in chemotherapy\u2010resistant CRC, where it undermines treatment by suppressing MDR2 protein degradation. Mechanistically, we discovered POU2F1 stimulates MCT4 expression, which in turn triggers the cytosolic lactate export, where decreases the level of PPP1R11 lactylation, a negative regulator of MDR2. Further experiments unveil that lactylation of PPP1R11, a critical post\u2010translational modification that normally stabilizes PPP1R11 and boosts its E3 ligase activity, promotes MDR2 ubiquitination and degradation, sensitizing cells to chemotherapy. Overall, our findings highlight the ability of POU2F1 in chemoresistance and regulating protein lactylation. 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