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Shikonin demonstrates multifaceted pharmacological profiles, encompassing analgesic, anti\u2010inflammatory, antineoplastic, and hemostatic activities. Notably, Shikonin has demonstrated significant inhibitory activity against a variety of malignancies, particularly offering promising strategies for addressing Nano\u2010based strategy, Pyruvate kinase M2 (PKM2), shikonin, tumor metabolism, and drug\u2010resistant cancers. This review systematically synthesizes the latest advancements in Shikonin's anti\u2010cancer efficacy, providing a theoretical foundation and future directions for its mechanisms, clinical applications, and nano\u2010based 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\u2010based 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\u2010specific delivery of Shikonin. Bioengineered cell\u2010derived 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\u2010materials for its delivery is crucial. Nevertheless, the application of nano\u2010therapy 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\u2010therapy will be a key focus for future research.<\/jats:p>","DOI":"10.1002\/adhm.202503750","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T08:35:04Z","timestamp":1764146104000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular Pathway Modulation and Nanotechnology\u2010Based Therapeutic Strategies for Shikonin"],"prefix":"10.1002","volume":"15","author":[{"given":"Haibo","family":"Wang","sequence":"first","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4709-7378","authenticated-orcid":false,"given":"Qiwei","family":"Tian","sequence":"additional","affiliation":[{"name":"Shanghai University of Traditional Chinese Medicine  Shanghai 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Shanghai for Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Normal University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Huang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Molecular Imaging Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104463"},{"key":"e_1_2_11_3_1","first-page":"4127","article-title":"Advances in Studies on Chemical Compositions and Pharmacological Activities of Arnebiae Radix","volume":"40","author":"Zhan Z.\u2010L.","year":"2015","journal-title":"China Journal of Chinese Materia Medica"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2014.2771"},{"key":"e_1_2_11_5_1","article-title":"Shikonin Inhibits Non\u2010Small\u2010Cell Lung Cancer H1299 Cell Growth through Survivin Signaling Pathway","volume":"2021","author":"Wang H.","year":"2021","journal-title":"Anal Cell Pathol (Amst)"},{"key":"e_1_2_11_6_1","first-page":"415","article-title":"The Effects of 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