Shikonin as a Dietary Phytochemical with Multi-Target Anti-Cancer Activities: From Molecular Mechanisms to Translational Applications

Shikonin, a naphthoquinone from Lithospermum erythrorhizon, exhibits broad anticancer potential through multiple regulated cell death pathways. It induces apoptosis via mitogen-activated protein kinase (MAPK) signalling, reactive oxygen species (ROS) accumulation, endoplasmic reticulum (ER) stress, and p53 activation, and also triggers necroptosis through receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL), as well as ferroptosis and pyroptosis. Beyond cytotoxicity, shikonin suppresses metastasis by blocking epithelial–mesenchymal transition (EMT) and downregulating matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). It further disrupts tumour metabolism by targeting pyruvate kinase isoform M2 (PKM2) and modulating the Warburg effect. In combination, shikonin enhances the efficacy of chemotherapy (cisplatin, paclitaxel), targeted therapy (tamoxifen), and immunotherapy (anti-programmed cell death protein 1 [anti-PD-1]), thereby overcoming resistance. To address poor bioavailability, nanoparticles, liposomes, and derivatives such as β, β-dimethylacrylshikonin have been developed to improve potency and reduce toxicity. Preclinical studies show strong tumour regression in melanoma, breast, and ovarian cancer models. Although clinical validation remains limited, shikonin’s multifaceted actions, favourable safety, and therapeutic synergy highlight the need for rigorous clinical trials to define its oncological value.