Medicarpin triggers Fas cell surface death receptor-mediated apoptosis by inhibiting epidermal growth factor receptor/signal transducer and activator of transcription 3 pathway and protective autophagy in liver cancer.
BACKGROUND Liver cancer remains the leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutics. Medicarpin is a pterocarpan, an isoflavonoid derivative, isolated from Spatholobus suberectus Dunn, exhibiting diverse bioactivities, yet its anticancer potential in liver cancer and underlying mechanisms are not well characterized. PURPOSE This study aims to investigate the therapeutic efficacy of medicarpin against liver cancer and to elucidate its molecular mechanisms, focusing on its interplay with the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 3 (STAT3) signaling and autophagy regulation. METHODS A series of in vitro and in vivo assays were conducted to assess medicarpin's effects on apoptosis, EGFR stability, STAT3 signaling and autophagy in liver cancer cells. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability were employed to confirm target engagement. In vivo efficacy was evaluated using HepG2 xenograft models. RESULTS Medicarpin selectively induced apoptosis in liver cancer cells while sparing normal hepatocytes. This effect was independent of p53 status and was mediated through upregulation and membrane accumulation of Fas (Fas cell surface death receptor). Mechanistically, medicarpin directly bound to EGFR, promoted its ubiquitin-mediated degradation, and consequently suppressed the EGFR-STAT3 signaling pathway. Furthermore, medicarpin concurrently triggered protective autophagy, and its inhibition synergistically enhanced its cytotoxicity. In xenograft models, medicarpin significantly suppressed tumor growth. CONCLUSION Our findings identify medicarpin as a novel EGFR‑modulating natural compound that induces Fas-mediated apoptosis in liver cancer, independent of p53 status. The concomitant induction of protective autophagy presents a rational combinatory strategy to enhance its therapeutic efficacy. This study underscores the translational potential of medicarpin as a promising candidate for phytotherapy-based liver cancer treatment.