Shikonin: Unraveling its Multi-Mechanistic Anticancer and Anti- Inflammatory Mechanisms

Shikonin, a naphthoquinone secondary metabolite derived from the dried roots of Lithospermum erythrorhizon Sieb. et Zucc. (family Boraginaceae), has garnered significant attention in natural drug development due to its diverse pharmacological activities, including anti-inflammatory, immunomodulatory, and anti-tumor effects. Its anti- inflammatory and immunomodulatory properties are primarily mediated through the inhibition of key signaling pathways, such as NF-κB and MAPK, leading to the reduced expression of pro-inflammatory cytokines like TNF-α and IL-8, and the modulation of Th17/Treg cell balance, thereby ameliorating pathological processes in autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease. As a prominent naphthoquinone, shikonin exerts its anti-cancer effects via multiple mechanisms, inducing tumor cell apoptosis, inhibiting proliferation and metastasis, and interfering with glycolytic metabolism. These actions collectively inhibit angiogenesis and remodel the tumor microenvironment. Despite its high efficacy and broad-spectrum anti-cancer activity in vitro, the clinical application of shikonin is constrained by potential toxicity. Consequently, structural modifications (e.g., optimizing hydroxyl substituents) are imperative to improve its selectivity and safety. This article comprehensively elucidates the multi-- target mechanisms of shikonin in regulating the inflammation-immune network and in cancer treatment, underscoring its "one drug, multiple effects" characteristic. Our findings provide a theoretical foundation and propose translational strategies for developing shikonin as a novel immunomodulator and a low-toxicity naphthoquinone-based anticancer agent.