目的 探討線紋香茶菜醇提物（ILEE）對(duì)CCl₄誘導(dǎo)的小鼠肝纖維化的作用及其機(jī)制。方法 建立超高效液相色譜四級(jí)桿飛行時(shí)間串聯(lián)質(zhì)譜（UPLC-Q-TOF/MS）結(jié)合UNIFI平臺(tái)的分析方法，表征ILEE的化學(xué)成分。將昆明小鼠隨機(jī)分為對(duì)照組、模型組、秋水仙堿（陽(yáng)性藥，0.20 mg·kg^-1）和ILEE高、中、低劑量（16.28、8.14、4.07 g·kg^-1）組，每組12只。除了對(duì)照組外，所有小鼠均ip 10% CCl4橄欖油溶液，劑量為4 mL·kg^-1，3 d 1次，連續(xù)6周，建立肝纖維化模型。從模型建立的第1天起，同時(shí)ig給藥，對(duì)照組和模型組小鼠ig 0.1%羧甲基纖維素鈉溶液（20 mL·kg^-1），其余各組小鼠ig對(duì)應(yīng)的藥物，每天1次，連續(xù)6周。試劑盒法檢測(cè)血清丙氨酸氨基轉(zhuǎn)移酶（ALT）、天冬氨酸氨基轉(zhuǎn)移酶（AST）、Ⅲ型前膠原（PC-Ⅲ）、Ⅳ型膠原（COL-Ⅳ）、層黏蛋白（LN）和透明質(zhì)酸（HA）水平；觀察肝組織病理形態(tài)學(xué)變化。采用UPLC-MS/MS技術(shù)檢測(cè)對(duì)照組、模型組和ILEE高劑量組小鼠肝臟代謝物的變化，并進(jìn)行差異代謝物篩選。采用網(wǎng)絡(luò)藥理學(xué)對(duì)化學(xué)成分和差異代謝物進(jìn)行整合分析。結(jié)果 共鑒定了24個(gè)化學(xué)成分；與模型組相比，ILEE高、中劑量顯著降低了血清中ALT、AST、PC-Ⅲ、COL-Ⅳ、LN和HA水平（P＜0.05、0.01、0.001）；病理切片顯示，ILEE各劑量均減輕了肝細(xì)胞腫大、炎癥細(xì)胞浸潤(rùn)和纖維化程度。代謝組學(xué)分析表明，ILEE高劑量對(duì)肝纖維化小鼠肝臟中13種差異代謝物具有顯著回調(diào)作用。整合分析顯示異澤蘭黃素、迷迭香酸、丹酚酸B、laxiflorin B等9個(gè)成分可能作用于胸苷酸合成酶（TYMS）、酪氨酸酶（TYR）、醛酮還原酶家族1成員A1（AKR1A1）等17個(gè)靶點(diǎn)，影響酪氨酸代謝、糖酵解/糖異生和葉酸的一碳代謝通路，調(diào)節(jié)肝纖維化小鼠肝臟中維生素B₉、甲狀腺素、鄰羥基苯乙酸和2-磷酸-D-甘油酸的水平。結(jié)論 ILEE對(duì)CCl₄所致小鼠肝纖維化具有良好的防治作用，其機(jī)制可能與酪氨酸代謝、糖酵解/糖異生和葉酸的一碳代謝通路等途徑有關(guān)。

Objective To investigate the anti-liver fibrosis effects and the underlying mechanisms of the ethanol extract of Isodon lophanthoides (ILEE) on CCl₄-induced liver fibrosis in mice.Methods An analytical method based on ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) combined with the UNIFI platform was established to characterize the chemical constituents of ILEE. KM mice were randomly divided into a control group, a model group, a colchicine (positive drug, 0.20 mg·kg^-1) group, and high-, medium-, and low-dose ILEE groups (16.28, 8.14, and 4.07 g·kg^-1), with 12 mice in each group. Except for the control group, all mice were intraperitoneally injected with 10% CCl₄ olive oil solution at a dose of 4 mL·kg^-1 once every 3 days for six consecutive weeks to establish a liver fibrosis model. From the first day of model establishment, intragastric administration was simultaneously given. Mice in the control and model groups were intragastrically administered 0.1% sodium carboxymethyl cellulose solution (20 mL·kg^-1), while mice in the other groups were intragastrically administered the corresponding drugs once a day for 6 consecutive weeks. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, type III procollagen (PC-III), type IV collagen (COL-IV), laminin (LN), and hyaluronic acid (HA) were measured. Liver tissue pathological changes were also observed. UPLC-MS/MS technology was employed to assess changes in liver metabolites across the control, model, and high-dose groups, enabling differential metabolite screening. Network pharmacology was employed to perform an integrated analysis of the chemical components and differential metabolites.Results A total of 24 chemical components were identified. Compared with the model group, the high-and medium-dose ILEE significantly reduced the serum levels of ALT, AST, PCIII, COL-IV, LN, and HA (P<0.05, 0.01, 0.001). Pathological sections revealed that ILEE at high, medium, and low doses reduced hepatocyte enlargement, inflammatory cell infiltration, and fibrosis. Metabolomic analysis demonstrated that high doses of ILEE significantly reversed 13 differential metabolites in the livers of mice with liver fibrosis. Integrated analysis indicated that nine components including eupatilin, rosmarinic acid, salvianolic acid B, and laxiflorin B, may act on 17 targets such as TYMS, TYR, and AKR1A1, affecting tyrosine metabolism, glycolysis/gluconeogenesis, and one carbon pool by folate, regulating the levels of vitamin B9, thyroxine, 2-hydroxyphenylacetic acid, and 2-phospho-D-glyceric acid in the livers of mice with liver fibrosis.Conclusion ILEE exhibits significant preventive and therapeutic effects on CCl₄-induced liver fibrosis in mice, with its mechanism may be associated with tyrosine metabolism, glycolysis/gluconeogenesis, and the one carbon pool by folate.

R285.5

廣西科技基地與人才專項(xiàng)（桂科AD21238032）；廣西青年科學(xué)基金資助項(xiàng)目（2023GXNSFBA026276）；國(guó)家重大新藥創(chuàng)制科技重大專項(xiàng)資助項(xiàng)目（2019ZX09201004）；廣西中醫(yī)藥大學(xué)博士科研啟動(dòng)項(xiàng)目（2020BS015）；廣西中醫(yī)藥大學(xué)青年科學(xué)基金資助項(xiàng)目（2021QN006，2024QN47）；廣西中醫(yī)藥大學(xué)第三批“岐黃工程”高層次人才團(tuán)隊(duì)培育項(xiàng)目（202406）