Formononetin inhibits colorectal cancer.

Formononetin inhibits colorectal cancer via the miR-490-3p/ABCC2 axis and synergizes with 5-fluorouracil: mechanistic insights and therapeutic implications.

Hyung Eun Yu, Moonkyoo Kong, Jing-Hsien Chen, Jingwen Liu, Kai Shan, Guang-Xian Zhang, Ren-Wang Jiang, Ying Zheng, Qiaoling Chen, Ruiwen Zhang, Zhuo-lin Liu, Jingdan Wu

Biochem Pharmacol

Dec 2, 2025

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Abstract

Colorectal cancer (CRC), one of the primary causes of gastrointestinal malignancy-related mortality worldwide, encounters significant therapeutic challenges due to multidrug resistance. Multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2, plays a crucial role in the development of drug resistance during clinical CRC treatment. This study elucidates a novel mechanism by which formononetin (FMNT), a bioactive isoflavone commonly found in food and medicinal-related plants, suppresses CRC via microRNA-490-3p (miR-490-3p)-mediated regulation of ABCC2 and synergizes with 5-fluorouracil (5-FU). HCT116 and SW480 cell lines as well as AOM/DSS-induced CRC models in wild-type and Mrp2mice were employed. The results demonstrated that FMNT markedly suppresses CRC proliferation in vitro and tumorigenesis in vivo. Transcriptomic profiling identified ABCC2 as the top target associated with FMNT's efficacy. This finding was validated in clinical specimens, which revealed significant upregulation of MRP2 in human CRC tissues. FMNT markedly downregulated the MRP2 expression. Genetic ablation experiments further confirmed enhanced FMNT sensitivity in Mrp2mice and MRP2 silencing CRC cells. Mechanistically, FMNT upregulated tumor-suppressive miR-490-3p, which directly targets the ABCC2 3'UTR, thereby establishing a regulatory axis corroborated by gain/loss-of-function experiments. Notably, overexpression of miR-490-3p augmented FMNT's antitumor effects, whereas inhibition of miR-490-3p diminished its efficacy. Therapeutic combination index analysis indicated robust synergy between FMNT and 5-FU, with combination therapy achieving superior tumor growth inhibition compared to monotherapies. Collectively, our findings uncover a novel miR-490-3p/ABCC2 regulatory mechanism underlying FMNT's antitumor activity and highlight its potential for chemosensitization through ABCC2 inhibition, providing a strong rationale for flavonoid-based adjuvant therapy in CRC management.