Molecular Pathway Modulation and Nanotechnology‐Based Therapeutic Strategies for Shikonin

Chinese herbal medicine Radix lithospermi (Lithospermum erythrorhizon), a traditional medicinal herb widely utilized in China, yields Shikonin as a bioactive monomeric compound. Shikonin demonstrates multifaceted pharmacological profiles, encompassing analgesic, anti-inflammatory, antineoplastic, and hemostatic activities. Notably, Shikonin has demonstrated significant inhibitory activity against a variety of malignancies, particularly offering promising strategies for addressing Nano-based strategy, Pyruvate kinase M2 (PKM2), shikonin, tumor metabolism, and drug-resistant cancers. This review systematically synthesizes the latest advancements in Shikonin's anti-cancer efficacy, providing a theoretical foundation and future directions for its mechanisms, clinical applications, and nano-based treatment optimizations. Shikonin acts as a selective PKM2 inhibitory agent, modulating tumor metabolism and regulating critical signaling pathways to mediate its antitumor activity. Shikonin exerts anticarcinogenic effects through suppressing neoplastic cell growth, triggering programmed cell death, halting cell cycle progression, enhancing autophagic activity, and inhibiting metastatic dissemination. However, the targetability, cellular permeability, and in vivo safety of Shikonin are critical limitations restricting its clinical application. Therefore, nano-based therapeutic strategies involving Shikonin, where it is integrated with nanoparticles, nanocarriers, nanoliposomes, and other nanomaterials to enhance immunotherapy and targeted therapy outcomes. To address the current limitations, modifying nanocarriers with chemical groups, antibodies, peptides, or aptamers can improve the precision of tumor-specific delivery of Shikonin. Bioengineered cell-derived nanoscale vesicles for Shikonin delivery can enhance biocompatibility and reduce the risk of immune rejection. However, due to the inherent toxicity of Shikonin itself and its pharmacokinetic properties, the use of nano-materials for its delivery is crucial. Nevertheless, the application of nano-therapy with Shikonin is still at the stage of cellular and animal experiments. Extensive preclinical research is needed to evaluate the combination of Shikonin with advanced treatment modalities to determine the optimal synergistic effects and avoid adverse interactions. Due to the lack of clinical studies, enhancing clinical research on nano-therapy will be a key focus for future research.