作者: Liao, Yufen ; Peng, Ying ; Liu, Ting ; Pan, Jie ; Tan, Rong ; Gong, Bowen ; Zhang, Enfu ; Hu, Zixia ; Zhang, Shiyu ; Li, Weiwei ; Wu, Chutian ; Zheng, Jiang ; Ding, Yuan

Dictamni Cortex (DC) has been associated with herb-induced liver injury, and fraxinellone (FRA), a furan-containing constituent, is implicated as a major hepatotoxic component. However, direct evidence linking FRA bioactivation to hepatic protein adduction in vivo remains limited. Here, we synthesized pyrroline- and pyrrole-type conjugates derived from the reactive FRA-cis-enedial intermediate and established liquid chromatography-tandem mass spectrometry methods to quantify corresponding lysine and cysteine/lysine adduct markers in the mouse liver after oral dosing with FRA or DC extract. Protein adduct levels increased in a dose- and time-dependent manner, peaked at 12 hours, and remained detectable up to 120 hours. Pretreatment with the CYP3A inhibitor ketoconazole markedly reduced adduct formation, supporting a CYP3A-dependent bioactivation pathway. To enable immunochemical detection, oxidized FRA was coupled to keyhole limpet hemocyanin to generate a polyclonal antiserum that selectively recognized FRA-derived pyrroline and pyrrole motifs. Western blotting and immunofluorescence revealed increased immunoreactive bands and a pericentral (central vein > portal triad) gradient in liver lobules, with prominent nuclear staining in hepatocytes after FRA or DC extract exposure; these signals were attenuated by ketoconazole. Collectively, these data demonstrate that CYP3A-mediated formation of an electrophilic cis-enedial intermediate drives covalent modification of hepatic proteins during FRA/DC exposure. The combined liquid chromatography-tandem mass spectrometry and antibody-based assays provide complementary tools for mechanistic studies and biomarker development for furan-containing herbal constituents. SIGNIFICANCE STATEMENT: This work provides direct in vivo evidence that CYP3A-dependent bioactivation of fraxinellone generates a reactive cis-enedial that covalently modifies hepatic proteins. The liquid chromatography-tandem mass spectrometry adduct markers and a selective antiadduct antibody enable semi‑quantitative detection and spatial mapping of protein adduction, supporting mechanistic investigations and biomarker development for furan-containing herbal constituents associated with liver injury.

2026-02-01·JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY

Fraxinellone Inhibited Immune Evasion and Cell Growth by Inactivating HIF‐1α/STAT3/PD‐L1 Signaling in Esophageal Squamous Cell Carcinoma

Article

作者: Bian, Bo ; Zhang, Guangji ; Bian, Hua ; Wang, Qian ; Li, Kai ; Duan, Peipei ; Zhang, Lifang

ABSTRACT:

Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype constituting approximately 80% of all esophageal malignancies worldwide, represents a significant global disease burden with distinct geographical predilection. Fraxinellone (FRA) was reported to function as a tumor suppressor in several tumors, while the role of FRA in ESCC remains unclear. In the present study, we found that FRA treatment significantly inhibited cell proliferation and colony formation of ESCC cells. On the contrary, FRA treatment promoted cell apoptosis of ESCC cells by downregulating Bcl‐2 protein and upregulating Bax and C‐caspase3 proteins. Besides, FRA pretreatment suppressed proliferation and viability of CD8 + T cells but facilitated cell apoptosis in co‐culturing system. Moreover, FRA pretreatment restrained immune evasion by attenuating CD8 + T cell activation. Mechanistically, FRA effectively inactivated HIF‐1α/STAT3/PD‐L1 signaling in ESCC cells and xenograft tumors. Ultimately, FRA treatment inhibited tumor growth in vivo. In conclusions, FRA inhibited ESCC cell growth and immune evasion by inactivating HIF‐1α/STAT3/PD‐L1 signaling in vitro and vivo. This study suggested that FRA may serve as a potential therapeutic agent for ESCC treatment.

2026-01-01·PHYTOMEDICINE

Elucidation of Cortex Dictamni hepatotoxicity mechanism by integrated serum pharmacochemistry and metabolomics

Article

作者: Liu, Sujie ; Ruan, Jiaxin ; Yan, Jiahe ; Wang, Xiaofan ; Wang, Chen ; Chen, Pingping ; Wang, Yu ; Na, Zhang ; Liu, Shumin ; Yu, Donghua ; Lu, Fang

OBJECTIVE:

To provide a panoramic analysis of Cortex Dictamni (DIC) and to elucidate the potential toxic components and mechanism of action of DIC-induced hepatotoxicity.

METHODS:

Liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) was used to identify serum components, and network toxicology, molecular docking and molecular dynamics simulations were combined to identify potentially toxic components and targets. In vivo experiments were performed using rats, which were divided into a control group (Con group) and groups treated with DIC-l (0.9 g/kg), DIC-M (2.7 g/kg), DICH (8.1 g/kg), and isoniazid (INH) (100 mg/kg) via gavage for 14 d Biochemical indices, hepatic tissue pathology, hepatic function parameters, and apoptosis markers were systematically evaluated to assess hepatic toxicity. Hepatotoxicity was also assessed by metabolomics analysis. The changes in the serum metabolic profiles during the administration period and after drug withdrawal were analyzed by metabolomics to determine the mechanism of metabolic pathway perturbation in DIC-induced liver injury. Finally, BRL 3A cells were used to verify the in vitro toxicity of DIC, and the mechanism of DIC hepatotoxicity was comprehensively explained by a combination of in vivo and in vitro experiments.

RESULTS:

Thirty-four prototypical components, including alkaloids, terpenoids, flavonoids and other compounds, were successfully identified from DIC. Through network toxicology analysis, molecular docking and molecular dynamics simulation, dictamnine and fraxinellone were identified as potential key components mediating the hepatotoxicity of DIC; this toxicity may be mediated through the PI3K/AKT signaling pathway. Animal experimental data revealed that after 14 d of treatment, the rats in all the dosage groups presented different degrees of hepatic injury, and the serum levels of AST, ALT and ALP were significantly increased, confirming the hepatotoxicity of DIC. Metabolomic studies further revealed that DIC induced liver injury by interfering with bile acid metabolism, lipid metabolism and sphingolipid metabolism. Mechanistic validation experiments revealed that dictamnine and fraxinellone activated the PI3K/AKT signaling pathway and promoted the apoptosis of hepatocytes, thus mediating the hepatotoxicity.

CONCLUSION:

This study is the first to analyze the components of DIC using serum medicinal chemistry to identify the main toxicants and to elucidate the potential molecular mechanism of DIC-induced hepatotoxicity. The results of this study provide an important theoretical basis for further investigations of the mechanism of DIC toxicity and the development of toxicity reduction strategies. These results are also important for promoting the safe use of DIC and the modernization of traditional Chinese medicine.

项与 Fraxinellone 相关的新闻（医药）

2026-08-10

·今日头条

破解肝脏纤维化细胞交互密码，白鲜皮或能有效填补肝病特效药空白

慢性肝病进展至肝纤维化、乃至肝硬化和肝癌，是全球范围内的重要健康负担。肝纤维化的本质是肝脏对慢性损伤的异常修复反应，在这一过程中，肝星状细胞的持续活化导致细胞外基质过度沉积，最终破坏肝脏正常结构。目前，临床上尚缺乏能够直接阻断纤维化进程的获批药物，近年上市的瑞司美替罗也主要侧重于代谢调节，对中晚期纤维化效果有限。因此，寻找直接干预纤维化信号通路的策略一直是研究热点。近日，来自南京大学医学院附属鼓楼医院的科学团队在国际知名期刊Acta Pharmacologica Sinica上在线发表了一篇题为“Macrophage FOLR2 drives liver fibrosis via intercellular engagement of TGFβRII”的研究性论文，首次揭示巨噬细胞表面蛋白FOLR2可通过直接结合肝星状细胞上的TGFβRII受体，持续驱动促纤维化信号输出；同时证实从中药白鲜皮中提取的天然化合物梣酮能有效阻断该相互作用，从而显著缓解肝纤维化。梣酮是一种来源于芸香科植物白鲜干燥根皮的四氢苯并呋喃类天然化合物。该成分具有抗炎、抗氧化及抗肿瘤等多种药理活性，但高浓度时可能存在肝毒性，需严格控制剂量。研究显示，在人和小鼠的纤维化肝脏中，表达FOLR2的修复型巨噬细胞与活化的肝星状细胞在空间上紧密相邻。这种邻近关系并非偶然，而是具有直接的功能意义：巨噬细胞表面的FOLR2能够与肝星状细胞表面的转化生长因子β受体II（TGFβRII）发生物理性结合，从而持续增强TGF-β1下游信号，驱动肝星状细胞活化并大量产生胶原蛋白。通过基因敲除小鼠实验，研究者证实去除FOLR2可显著减轻四氯化碳诱导的肝胶原沉积和炎症损伤，明确了 FOLR2是肝纤维化进程中一个关键的调控节点。针对这一靶点，研究者从传统中药白鲜皮中提取了天然化合物梣酮，并通过反向虚拟筛选和分子互作实验证实其可直接结合FOLR2蛋白。梣酮能够有效阻断FOLR2与TGFβRII之间的相互作用，进而抑制巨噬细胞对肝星状细胞的活化刺激。在动物模型中，梣酮口服给药显著改善了小鼠的肝纤维化程度，而在FOLR2基因敲除小鼠中则无额外保护效应，充分表明梣酮的抗纤维化作用严格依赖于其对FOLR2的靶向干预。综上，文章首次揭示了 FOLR2通过直接细胞间受体结合驱动肝纤维化的全新机制，并表明梣酮作为天然来源的FOLR2抑制剂，为开发直接靶向纤维化信号的治疗药物提供了明确的理论基础和先导化合物。这一发现不仅彰显了中药活性成分在现代药物研发中的独特价值，还为无数肝病患者带来了可期的临床转化前景。参考文献： https://doi.org/10.1038/s41401-026-01878-7

100 项与 Fraxinellone 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
肝纤维化	临床前	中国	中国药科大学	2026-07-30
肝纤维化	临床前	中国	山东大学	2026-07-30
阿尔茨海默症	临床前	印度	GLA University	2024-08-06
帕金森病	临床前	印度	GLA University	2024-08-06