{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T09:02:55Z","timestamp":1779699775442,"version":"3.53.1"},"reference-count":50,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":">National Science and Technology Major Project of China","award":["2025D18043047"],"award-info":[{"award-number":["2025D18043047"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The clinical application of Polygonum multiflorum Thunb. (PM), a widely used traditional Chinese medicine, is increasingly constrained by its idiosyncratic hepatotoxicity. However, the precise chemical material basis (i.e., specific compound classes such as free anthraquinones, stilbene glycosides, and dianthrones) of this toxicity and the underlying synergistic mechanisms remain poorly defined, posing a significant challenge to safety assessment. This review systematically synthesizes the latest research progress over the past five years, aiming to elucidate the multi-component synergistic toxicity network of PM. As of November 2025, over 293 compounds have been characterized from PM, including anthraquinones, stilbene glycosides, and dianthrones. Among these, multiple components\u2014particularly free anthraquinones (e.g., emodin, chrysophanol, physcion), cis-stilbene glycosides, and dianthrones\u2014have been experimentally associated with hepatotoxicity in various in vitro and in vivo studies. However, current evidence is largely derived from in vitro or animal studies, and the quantitative nature of these synergistic interactions, as well as their translation to human clinical settings, remains uncertain. Accumulating evidence indicates that its hepatotoxicity does not originate from a single component but rather results from the synergistic interaction of free anthraquinones, stilbene glycosides, and dianthrones. At the mechanistic level, the toxicity involves a complex network encompassing direct cellular damage, an immune-mediated \u201ctriple-hit\u201d cascade, and disruption of bile acid homeostasis. Importantly, traditional processing methods mitigate toxicity by reducing the content of specific toxic components, whereas individual genetic susceptibility (e.g., HLA-B*35:01 allele) appears to be an important contributing factor, although population-based quantitative risk estimates are still lacking in the occurrence of idiosyncratic liver injury. In conclusion, the hepatotoxicity of PM constitutes a multi-component, multi-target, and multi-pathway synergistic network. Future research should prioritize quantifying the toxic contribution of individual components and elucidating the quantitative principles governing their synergy, thereby establishing a robust paradigm for risk assessment.<\/jats:p>","DOI":"10.3390\/ijms27114733","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"4733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatotoxic Compounds and Mechanisms of Polygonum Multiflorum: A Narrative Review of Recent Advances"],"prefix":"10.3390","volume":"27","author":[{"given":"Yupeng","family":"Wang","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Research on Quality and Standardization of Biotech Products and NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute for Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqi","family":"Ren","sequence":"additional","affiliation":[{"name":"National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing 100176, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8106-8820","authenticated-orcid":false,"given":"Yikun","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing 100176, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyong","family":"Yuan","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Research on Quality and Standardization of Biotech Products and NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute for Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1605-2937","authenticated-orcid":false,"given":"Xingchao","family":"Geng","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Research on Quality and Standardization of Biotech Products and NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute for Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1039\/D4AN00964A","article-title":"Ti-based MOF nanosheets as a mass spectrometry imaging matrix for low molecular weight compounds to reveal the spatiotemporal content changes of hepatotoxic components during the processing of Polygonum multiflorum","volume":"150","author":"Kuang","year":"2024","journal-title":"Analyst"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1007\/s00216-024-05177-0","article-title":"A comprehensive investigation on the chemical changes of traditional Chinese medicine with classic processing technology: Polygonum multiflorum under nine cycles of steaming and sunning as a case study","volume":"416","author":"Fan","year":"2024","journal-title":"Anal. 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