Silibinin: a natural flavonoid with multifaceted anticancer potential and therapeutic challenges

Abstract

Silibinin, the principal bioactive flavonolignan of Silybum marianum (milk thistle), has emerged as a promising natural agent with multifaceted anticancer potential. Extensive preclinical studies demonstrate its diverse pharmacological properties, including antioxidant, anti-inflammatory, and chemopreventive activities, which collectively contribute to its antitumor effects. At the molecular level, silibinin exerts cytotoxicity through the induction of apoptosis, involving both extrinsic (death receptor-mediated) and intrinsic (mitochondria-dependent) pathways. It modulates key signaling cascades such as EGFR, STAT3, and PI3K/AKT/mTOR, leading to suppression of proliferation, angiogenesis, invasion, and modulation of autophagy, stemness and Senescence. Importantly, silibinin acts as a modulator of apoptosis by restoring the balance between pro- and anti-apoptotic proteins, thereby sensitizing cancer cells to programmed cell death. Evidence across multiple malignancies, including hepatocellular carcinoma, breast, lung, and colorectal cancers etc, highlights its broad-spectrum therapeutic relevance. Clinical studies, though limited, suggest that silibinin may enhance the efficacy of standard chemotherapeutic, radiotherapeutic, and targeted regimens while reducing associated toxicities, underscoring its role as a synergistic adjuvant. However, challenges such as poor bioavailability, variable pharmacokinetics, and limited large-scale clinical validation constrain its translational application. To address these limitations, novel strategies such as nanocarrier-based delivery, structural modifications, and combination therapies are being actively investigated. Overall, silibinin represents a compelling natural flavonoid with dual preventive and therapeutic roles in oncology, though future research must overcome pharmacological barriers to fully harness its clinical potential. (Figure presented.) © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.