Curcumin Modulates 5-fluorouracil Sensitivity in Colorectal Cancer Cells Through the circ-NRIP1/miR-195-5p/SMURF1/AKT Signaling Axis.

Curcumin has demonstrated antitumor efficacy, and its therapeutic and adjunct potential is increasingly supported by evidence. However, the anticancer mechanisms of curcumin in combination with chemotherapy remain complex and heterogeneous, warranting further investigation. Although 5-fluorouracil (5-FU)-based chemotherapy remains a cornerstone of colorectal cancer (CRC) management, the emergence of chemoresistance significantly limits its clinical application. Therefore, the present work focused on elucidating the role of curcumin in modulating 5-FU sensitivity and exploring the underlying molecular mechanism. Initially, we validated the antitumor effects of curcumin both in vivo and in vitro, and demonstrated its synergistic efficacy when combined with 5-FU. We further identified circ-NRIP1 as a target of curcumin and confirmed that curcumin enhances 5-FU sensitivity in CRC cells by downregulating circ-NRIP1 level. Mechanistic studies revealed that circ-NRIP1 suppresses SMURF1 expression by competitively binding to miR-195-5p, leading to AKT pathway activation, inhibition of apoptosis, and ultimately reduced 5-FU sensitivity in CRC cells. Collectively, our findings verify that curcumin modulates 5-FU sensitivity in CRC to through the circ-NRIP1/miR-195-5p/SMURF1/AKT regulatory axis, providing a novel strategic approach for clinical CRC treatment.