Non-Apoptotic Inhibition of Colorectal Cancer Proliferation by Sclareol via Ferroptosis Involving SLC7A11/GPX4 Modulation

作者：Li YX, Wu Y, Li Q, Huang YQ, Yuan YY, Su YN, Cheng CS, Zheng L · 发表于：Phytotherapy research : PTR · 年份：2025 · 研究领域：Ferroptosis、Colorectal Neoplasms、Phospholipid Hydroperoxide Glutathione Peroxidase、Amino Acid Transport System y+、Diterpenes、Antineoplastic Agents, Phytogenic、Humans、Animals、Cell Proliferation、Mice、Reactive Oxygen Species、Cell Line, Tumor

Colorectal cancer (CRC) is a prevalent and lethal malignancy necessitating new treatments. Sclareol, the primary active component of Salvia sclarea L., exhibits diverse pharmacological properties, making it a promising anti-cancer drug warranting further investigation. To evaluate Sclareol's action in CRC cell death, various methods were performed, including cell viability and colony formation assays, EdU assay, flow cytometry for cell cycle analysis and apoptosis, as well as TUNEL staining, transmission electron microscopy (TEM), reactive oxygen species (ROS) detection, and Fe2+ fluorometric assay. RNA sequencing and pathway analysis, combined with in silico molecular docking, and immunoblotting, were conducted to determine the mechanism of action of Sclareol. A CRC xenograft model in immunocompetent mice was used to evaluate Sclareol's in vivo efficacy and toxicity, with immunohistochemistry confirming its mechanism of action. Sclareol significantly suppressed CRC cell proliferation and induced cell cycle arrest in vitro without significantly inducing apoptosis. Ferroptosis as a promising mechanism of action was validated through TEM, ROS detection, and Fe2+ staining. RNA sequencing analysis revealed enrichment in metal ion-transporter activity. Molecular docking analysis showed direct binding of Sclareol to the key ferroptosis-related target solute carrier family 7 member 11 (SLC7A11). Additionally, Sclareol downregulated the expression of SLC7A11, nuclear factor erythroid...