Puerarin Enhances the Sensitivity of Colorectal Cancer to 5‐Fluorouracil and Oxaliplatin by Inhibiting the PTEN/PI3K/AKT Signaling Pathway

ABSTRACT Colorectal cancer (CRC) represents the most prevalent malignancy within the gastrointestinal system, with metastatic cases comprising approximately 50% of all CRC diagnoses. While chemotherapy remains the cornerstone treatment for metastatic CRC, the emergence of chemoresistance has significantly limited the clinical efficacy of 5‐fluorouracil (5‐FU) and oxaliplatin‐based regimens. In this study, we systematically investigated the therapeutic potential of puerarin in CRC management, focusing on its antitumor properties and chemosensitization effects. Our findings demonstrate that puerarin exhibits significant antitumor activity both in vitro and in vivo, while also potentiating the therapeutic effects of 5‐FU and oxaliplatin through synergistic interactions. Mechanistically, we identified PTEN as a critical molecular target of puerarin, evidenced by the reversal of puerarin‐mediated effects upon PTEN knockdown. Further molecular characterization revealed that puerarin exerts its antitumor effects through PTEN‐mediated suppression of AKT activation and subsequent induction of apoptotic pathways. Importantly, we established that puerarin enhances CRC cell sensitivity to 5‐FU and oxaliplatin via modulation of the PTEN/PI3K/AKT signaling axis. These findings not only elucidate a novel molecular mechanism underlying puerarin's anti‐CRC activity but also provide a promising therapeutic strategy for overcoming chemoresistance in CRC treatment.