Aqueous extract of Solanum nigrum L. restrains colorectal cancer progression by blocking cancer-associated fibroblast-induced STAT3-Annexin A2 signaling.

BACKGROUND: Colorectal cancer (CRC) remains a significant clinical challenge, with progression largely driven by tumor microenvironment (TME) remodeling. Cancer-associated fibroblasts (CAFs), key stromal components, promote CRC progression and metastasis via paracrine signaling. Solanum nigrum L. (SNL), a traditional medicinal plant rich in steroidal glycoalkaloids, is recognized for its health-promoting potential.

PURPOSE: This study aimed to systematically investigate the bioactive chemical constituents of an aqueous SNL extract, evaluate its biological effects in multiple CRC models, and link the extract's chemical profile to its functional outcomes, focusing on elucidating its anti-metastatic molecular mechanisms.

METHODS: We evaluated the in vivo efficacy of SNL in subcutaneous xenograft, APCMin/+, and experimental metastasis models. Phytochemical analysis identified its major active components. By integrating single-cell RNA sequencing (scRNA-seq) of human CRC with TMT-based proteomics of CRC cells, we identified and validated key molecular targets of SNL. We employed drug-target interaction assays, genetic modulation, and molecular analyses to elucidate its mechanism of action.

RESULTS: SNL markedly inhibited tumor growth and lung/liver metastasis in vivo. Phytochemical analysis identified solasonine and solamargine as the major glycoalkaloids responsible for the biological activity. Multi-omics analysis identified Annexin A2 (ANXA2) as a key SNL-regulated target. Mechanistically, SNL disrupted CAF-induced signaling, reversed epithelial-mesenchymal transition (EMT), and suppressed invasion by modulating the STAT3-ANXA2-Cortactin axis. While SNL did not bind ANXA2 directly, its active components, solasonine and solamargine, directly interacted with STAT3, blocking its phosphorylation and nuclear translocation, thus repressing ANXA2 transcription. Reduced ANXA2 levels prevented the ANXA2-Cortactin complex formation and inhibited Src/Cortactin phosphorylation, thereby impairing cytoskeletal remodeling and cell motility. Genetic modulation confirmed ANXA2 as a functional mediator of SNL's anti-metastatic effects.

CONCLUSION: These findings provide molecular evidence supporting SNL as a source of multifunctional bioactives capable of reshaping the tumor microenvironment and highlight its potential as a plant-derived therapeutic candidate for metastatic colorectal cancer.