Shikonin, a natural bioactive compound derived from medicinal plants, demonstrates extensive pharmacological properties in traditional Chinese medicine, and exhibits significant therapeutic potential for modern diseases such as cancers and immune-related disorders. Over the past decades, research has focused on its anticancer, anti-inflammatory, and immunomodulatory activities. In vitro and in vivo studies have elucidated its mechanisms at cellular and molecular levels. Shikonin exerts antitumor effects by inducing multiple cell death modalities through caspase-3 activation, ROS generation, modulation of ATF3 expression, modulation of RIP1/RIP3 signaling, and activation of the BAX/caspase-3/GSDME pyroptosis axis. Furthermore, it suppresses tumor cell proliferation, inhibits metastasis, and blocks cell cycle progression by downregulating oncogenic c-Myc and MMP2 while upregulating the cell cycle inhibitor P21. It also enhances chemosensitivity via β-catenin modulation. Furthermore, shikonin inhibits PD-L1 expression through the NF-κB/STAT3 and NF-κB/CSN5 pathways, and mediates tumor immunomodulation as a result. Its anti-inflammatory capacity is attributed to the regulation of immune cells, signaling pathways (e.g., TLR4/MyD88/NF-κB), and pro-inflammatory cytokines (e.g., TNF-α, IL-6). The regulation of these processes thereby enhances anti-inflammatory responses in target organs and mitigates autoimmune diseases. This review systematically deciphers shikonin's mechanisms in tumor suppression, inflammation resolution, and immune regulation, offering novel insights for interdisciplinary research bridging oncology, immunology, and inflammation biology, and laying a foundation for advancing immune-modulating cancer therapies and autoimmune disease management.
Keywords: Anti-inflammation; Anticancer; Immunoregulation; Molecular Mechanisms; Pharmacology; Shikonin.