8-epi-Helenalin suppresses tumorigenesis and metastasis by modulating the STAT3/FAK signaling axis

Hepatocellular carcinoma (HCC) poses a significant global health challenge, highlighting the importance of discovering novel anticancer lead compounds from natural products. In this study, we isolated the sesquiterpene lactone 8-epi-helenalin from the dried flowers of Inula japonica. In vitro experiments demonstrated its potent antiproliferative activity against various tumor cell lines, including human HCC cells (HepG2). Using a zebrafish xenograft model, we further confirmed its in vivo efficacy in suppressing tumor growth and metastasis. Given its remarkable antitumor effects, we investigated the underlying mechanisms. Our findings reveal that 8-epi-helenalin exerts multitargeted anticancer activity by inducing apoptosis via signal transducer and activator of transcription 3 (STAT3) signaling pathway modulation, inhibiting tumor cell migration through suppression of focal adhesion kinase (FAK) signaling, triggering ferroptosis by increasing lipid reactive oxygen species (ROS) accumulation and reducing glutathione (GSH) levels, and suppressing tumor angiogenesis. In conclusion, 8-epi-helenalin inhibits HCC progression through multiple pathways and targets, demonstrating promising potential as a therapeutic candidate for HCC treatment.