{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:41:16Z","timestamp":1791218476515,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Project for the Construction of Inheritance Workshops of Famous Traditional Chinese Medicine Practitioners","award":["245 [2022]"],"award-info":[{"award-number":["245 [2022]"]}]},{"name":"The \u201cHundred-Thousand-Million\u201d Talent Project for Inheritance and Innovation of Traditional Chinese Medicine (Qihuang Project)\u2014Qihuang Scholar Program","award":["284"],"award-info":[{"award-number":["284"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Ziziphi Spinosae Semen (ZSS) is a traditional East Asian sedative\u2013hypnotic herb with over 2000 years of clinical application. Spinosin (SPI), a characteristic flavone-C-glycoside, is the official quality marker and principal bioactive constituent of ZSS. Despite extensive research on SPI in recent years, a timely, comprehensive review integrating its pharmacological mechanisms, pharmacokinetic barriers, and translational strategies remains absent. Herein, a systematic literature search was conducted up to 31 May 2026, and we synthesize all available evidence on SPI\u2019s chemical properties, natural sources, pharmacology, pharmacokinetics, toxicology, structural derivatives, and advanced drug delivery systems. Our analysis reveals that SPI exerts broad-spectrum pharmacological activities via multi-target modulation of serotonergic\/GABAergic neurotransmission, the ERK\/CREB\/BDNF axis, and the Nrf2\/HO-1 pathway. However, its clinical translation is severely hindered by extremely low oral bioavailability (&lt;1%) and limited blood\u2013brain barrier penetration due to poor aqueous solubility and P-glycoprotein-mediated efflux. Novel formulations have achieved up to 5-fold enhancement in oral bioavailability in preclinical models. While toxicological studies support a favorable safety profile, long-term toxicity and human pharmacokinetic data are lacking. This review critically discusses key translational bottlenecks and proposes evidence-based future directions to advance SPI as a natural neurotherapeutic agent.<\/jats:p>","DOI":"10.3390\/molecules31152567","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:05:42Z","timestamp":1784819142000},"page":"2567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Spinosin: A Critical Updated Review on Pharmacology, Pharmacokinetics, Toxicity and Translational Bottlenecks"],"prefix":"10.3390","volume":"31","author":[{"given":"Keer","family":"Lu","sequence":"first","affiliation":[{"name":"School of Basic Medical Science, Heilongjiang University of Chinese Medicine, No. 24 Heping Street, Xiangfang District, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congyao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Science, Heilongjiang University of Chinese Medicine, No. 24 Heping Street, Xiangfang District, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2963-6119","authenticated-orcid":false,"given":"Ji","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Science, Heilongjiang University of Chinese Medicine, No. 24 Heping Street, Xiangfang District, Harbin 150040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. 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