Revised: May 10, 2026
Accepted: June 2, 2026
Published online: July 27, 2026
Processing time: 109 Days and 21.9 Hours
Fuling Zexie decoction (FZD), in which Poria (PR) occupies the foremost position in the prescription hierarchy, is used to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, the pharmacodynamic contribution of PR to the effects of FZD remains unclear and the yield of PR from aqueous ex
To clarify the contribution of PR to the effects of FZD in MASLD treatment.
The contribution of PR to the therapeutic efficacy of FZD was evaluated in high-fat diet-fed MASLD rats. The mechanisms and active substances were explored by integrating metabolomics and serum pharmacochemistry.
FZD and FZD supplemented with PR dregs alleviated lipid accumulation and tissue fibrosis in MASLD, while FZD without PR (ZD) showed no effect. FZD uniquely altered 148 metabolites and five pathways. FZD exhibited 10 unique drug-derived components in blood, six of which were derived from PR. Moreover, 20 active components in FZD specifically regulated 17 MASLD-related targets, among which the key targets, including phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta, aldo-keto reductase family 1 member B10, and aldo-keto reductase family 1 member B1, were upregulated. Both the key active compounds of FZD and PR-derived compounds in FZD modulated pho
PR, a component of FZD, plays an irreplaceable role in treating MASLD, which may be attributed to the presence of diverse and distinctive components in FZD, along with its specific regulation of five pathways and 148 me
Core Tip: This study clarified the specific contribution of Poria (PR) as the “sovereign” drug in Fuling Zexie decoction (FZD) for metabolic dysfunction-associated steatotic liver disease. We confirmed that PR plays an irreplaceable role and its removal significantly weakened the therapeutic efficacy of FZD. The superior effects of FZD were attributed to diverse active components (six derived from PR), the specific regulation of five metabolic pathways (biotin, ascorbate/aldarate, alanine/aspartate/glutamate, inositol phosphate, and galactose metabolism), and 148 differential metabolites. Additionally, incorporating PR dregs enhanced antioxidant and anti-inflammatory activities, indicating that water-insoluble polysaccharides are key bioactive constituents.
- Citation: Tao YX, Gong DH, Yang H, Wang PQ, Tang YM, Zhou QD, Wang YY, Zhang Y, Chen WD, Yu J, Yang XX. Poria in Fuling Zexie decoction for treating metabolic dysfunction-associated steatotic liver disease: Underlying mechanisms and key bioactive substances. World J Hepatol 2026; 18(7): 121954
- URL: https://www.wjgnet.com/1948-5182/full/v18/i7/121954.htm
- DOI: https://dx.doi.org/10.4254/wjh.121954
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the most prevalent chronic liver disorder globally, affecting approximately 32.4% of the world’s population[1,2]. MASLD is not only strongly associated with type 2 diabetes, cardiovascular disease, and chronic kidney disease, but also constitutes a significant risk factor for progressive liver pathologies, including fibrosis, cirrhosis, and hepatocellular carcinoma[3,4]. Current therapeutic strategies primarily emphasize weight reduction, waist circumference management, improving insulin resistance, and preventing metabolic syndrome and diabetes, thereby ameliorating metabolic dysfunction-associated steatohepatitis and facilitating fibrosis regression. However, standardized pharmacological interventions for MASLD have not yet been established.
Fuling Zexie decoction (FZD), first documented in Zhang Zhong-Jing’s “Jingui Yaolue (Synopsis of Golden Chamber)” from the late Eastern Han Dynasty, is composed of Poria (PR), Alismatis Rhizoma, Cinnamomi Ramulus, Atractylodis Macrocephalae Rhizoma, Glycyrrhizae Radix, and Zingiberis Rhizoma Recens at a ratio of 8:4:2:2:3:4. This formula functions to warm yang, resolve fluid retention, fortify the spleen, and promote diuresis, therapeutic actions aligned with the phlegm-stasis pathogenesis of MASLD[5]. Pharmacological studies have confirmed that FZD alleviates renal injury in hyperuricemia mice by suppressing the Janus kinase 2/signal transducer and activator of transcription 3 pathway[6] and nod-like receptor protein 3 inflammasome, and improves hyperlipidemia in rats by modulating myeloperoxidase and nitric oxide[7]. Clinical studies have revealed that FZD effectively reverses glucose and lipid metabolism disorders[8].
Notably, PR, the “sovereign drug” (Jun herb) in FZD, is a traditional Chinese medicinal fungus characterized by a sweet and bland taste, a neutral nature, and tropism for the heart, lung, spleen, and kidney meridians. Traditionally employed for its diuretic, dampness-resolving, spleen-invigorating, and mind-calming properties[9], PR constitutes the primary active ingredient responsible for the formula’s pharmacological efficacy. Meanwhile, contemporary pharmacological investigations have revealed that PR exhibits hypoglycemic, hypolipidemic, hepatoprotective, and insulin-sensitizing effects. Our previous study confirmed that PR ameliorated MASLD by modulating mitochondrial function, with 15 of its active components demonstrated to localize within mitochondria. Furthermore, two specific ligands derived from PR, tumulosic acid and polyporenic acid C, were found to activate the mitochondrial protein Parkin, thereby enhancing mitophagy and subsequently alleviating dyslipidemia[10]. Thus, PR is frequently incorporated into classical formulations such as FZD to target glucolipid metabolic disorders.
PR serves as the ‘sovereign drug’ in FZD, occupying the foremost position in the prescription hierarchy, and is considered indispensable for its efficacy. However, our initial studies revealed a low yield of PR from aqueous extraction (approximately 3%). Interestingly, the aqueous extraction yield of PR was not increased after compatibility with other drugs in FZD. These observations indicate that a significant quantity of PR constituents cannot be effectively extracted, with the PR dregs inevitably being classified and discarded as processing waste. Consequently, the contribution of PR to the efficacy of FZD in treating MASLD, as well as its possible mechanisms of action and effective substances, warrants in-depth exploration.
This study aimed to evaluate the pharmacodynamic effects of FZD, FZD without PR (ZD), and FZD supplemented with PR dregs (FFZD) in a high-fat diet (HFD)-fed MASLD rat model. Serum pharmacochemistry and metabolomics analyses were conducted to identify the potential mechanisms and active substances, followed by validation using molecular docking and cellular experiments. The findings revealed the indispensable role of PR in FZD for treating MASLD, thereby providing a scientific basis for its clinical application and market development.
PR, Alismatis Rhizoma, Cinnamomi Ramulus, Atractylodis Macrocephalae Rhizoma, Glycyrrhizae Radix, and Zingiberis Rhizoma Recens were weighed and mixed at a ratio of 8:4:2:2:3:4. The mixture was then decocted twice with 10 volumes of water, each for 1 hour. After filtration to remove impurities, the filtrate was concentrated and lyophilized to obtain freeze-dried FZD powder. ZD was prepared following the same procedure but with the omission of PR. For the preparation of FFZD, PR powder was wrapped in a gauze bag and decocted together with the other herbs as described above. The filtrate and PR powder boiled in the gauze bag were then lyophilized to obtain freeze-dried powders, which were uniformly mixed to obtain FFZD. Ultra-performance liquid chromatography was used to determine the content of atractylenolide II in FZD and ZD, which was 8.55 mg/g and 8.62 mg/g, respectively. Details of the analytical procedure are provided in the Supplementary material, and the chromatograms are shown in Supplementary Figure 1.
Animals and experimental design: Ninety specific pathogen-free male Sprague-Dawley rats (8 weeks old, 200-220 g; quality certificate No. 430727230103047542) were obtained from Hunan Shrek Jingda Laboratory Animal Co., Ltd. (Changsha, China) and housed at 22 ± 2 °C and 60% relative humidity, with a 12-hour light/dark cycle. Following a one-week acclimatization period, the rats were randomly divided into nine groups (n = 6 per group): Normal control (NC), HFD, fenofibrate capsules (FC; 21 mg/kg/day), low-dose FZD (3.625 g/kg/day), high-dose FZD (14.5 g/kg/day), low-dose ZD (2.365 g/kg/day), high-dose ZD (9.45 g/kg/day), low-dose FFZD (3.625 g/kg/day of FFZD and 0.525 g/kg/day residue of PR), and high-dose FFZD (14.5 g/kg/day of FFZD and 1.05 g/kg/day residue of PR). Based on the human clinical dose (69 g/60 kg/day) and the standard body surface area conversion formula (human-to-rat conversion factor = 6.3), the equivalent rat dose of FZD was calculated to be 7.25 g/kg/day. The low-dose FZD group was set at half of this dose (3.63 g/kg/day), and the high-dose FZD was set at twice this dose (14.5 g/kg/day).
All treatments were administered once daily for 12 consecutive weeks. The NC group was fed a standard diet, while all other groups were fed a HFD for 12 weeks to induce MASLD. The NC and HFD groups received an equivalent volume of distilled water. All animal procedures were approved by the Ethical Committee on Animal Care and Experimentation of Yunnan University of Chinese Medicine (Approval No. R-062023206).
Sample collection: In the final week of the experiment, 24-hour urine samples were collected from rats housed in metabolic cages and stored at -80 °C. One hour after the final administration, rats were anesthetized with an injection of 3% sodium pentobarbital. Blood was collected from the abdominal aorta, and serum was separated by centrifugation (3500 rpm, 15 minutes). The livers were excised, weighed, and stored at -80 °C until analysis.
Assay of serum and liver biochemical parameters: The serum and liver levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT), aspartate transaminase (AST), tumor necrosis factor (TNF)-α, interleukin (IL-6), IL-1β, malondialdehyde, and superoxide dismutase (SOD) were measured according to the commercial kit instructions. Data were acquired using a SpectraMax Plus 384 microplate reader (Molecular Devices, Sunnyvale, CA, United States).
Histopathological assessment: Liver samples were fixed, paraffin-embedded, and sectioned into 4-µm thick slices using a microtome. Sections were stained with hematoxylin and eosin, mounted with neutral gum, and imaged using a light microscope (Olympus Corporation, Tokyo, Japan). For oil red O staining, liver samples were fixed, frozen at -20 °C, and sectioned into 8 μm thick slices using a freezing microtome. Sections were then fixed, stained with oil red O, counterstained with hematoxylin, mounted with glycerin gelatin, and imaged using a light microscope (Olympus Corporation, Tokyo, Japan). For fibrosis assessment, liver samples were fixed, paraffin-embedded, and sectioned into 4 μm thick slices. The sections were deparaffinized to the aqueous phase, stained with Weigert’s iron hematoxylin, differentiated, and counterstained with aniline blue to visualize collagen deposition. Pathological changes were observed and imaged under a light microscope (Olympus Corporation, Tokyo, Japan).
Sample preparation: Serum samples (100 μL) were mixed with 400 μL of extraction solvent (acetonitrile-methanol, 1:1, volume/volume). The mixture was vortexed for 30 seconds, subjected to ultrasonic extraction (40 kHz, 4 °C) for 30 minutes, and then centrifuged at 12000 rpm for 15 minutes at 4 °C. The resulting supernatant was collected, evaporated to dryness under a nitrogen stream, and reconstituted in 100 μL of acetonitrile-water (1:1, volume/volume) prior to ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) analysis. Urine samples were processed identically. Liver tissue samples (50 mg) were homogenized in 400 μL of methanol-water (4:1, volume/volume) using a tissue grinder (6 minutes, -10 °C, 50 Hz). The homogenates were then subjected to ultrasonication (30 minutes, 5 °C, 40 kHz) and centrifuged (12000 rpm, 15 minutes, 4 °C). The resulting supernatant was concentrated under a nitrogen stream, reconstituted in 100 μL of acetonitrile-water (1:1, volume/volume), and subsequently analyzed. Fecal samples (50 mg) were homogenized in 400 μL of pre-cooled methanol-water (4:1, volume/volume) using a tissue disruptor under cryogenic conditions. Subsequently, 600 μL of additional pre-cooled methanol-water (4:1, volume/volume) was added, followed by thorough mixing. The mixture was subjected to ultrasonication in an ice bath for 20 minutes, incubated at
UPLC-MS analysis: For further details, please refer to the Supplementary material.
Data preprocessing and analysis: Raw data were processed using MSDIAL for peak alignment, retention time correction, and peak area extraction. Metabolites were identified by matching accurate mass and tandem mass spectrometry fragments against databases (HMDB and METLIN). Data were filtered, normalized, and subjected to multivariate statistical analysis, mainly orthogonal partial least squares-discriminant analysis (OPLS-DA). Significantly different metabolites were selected based on a variable importance in projection value of > 1.0 and a P-value of < 0.05 in the Student’s t-test. Pathway enrichment analysis was performed using MetaboAnalyst 5.0 based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. An impact value of > 0.1 was considered indicative of a key pathway.
Identification of FZD/FFZD/ZD-derived components in serum from MASLD rats: For further details, please refer to the Supplementary material.
Correlation analysis of FZD/ZD-derived components and metabolomics: The targets of FZD/ZD-derived components in serum were predicted using PubChem (https://pubchem.ncbi.nlm.nih.gov/) and SwissTargetPrediction (http://swisstargetprediction.ch/). MASLD-related targets were retrieved from GeneCards (https://www.genecards.org/) and OMIM Gene Map (https://www.omim.org/) databases. Additionally, FZD/ZD targets related to metabolic pathway regulation were obtained from the KEGG (https://www.kegg.jp/kegg/pathway.html) website. Venny 2.1.0 (http://www.liuxiaoyuyuan.cn/) software was used to obtain the overlapping targets of FZD/ZD-derived components, MASLD, and metabolic pathways. Finally, Cytoscape was used to construct an active ingredient-target-metabolic pathway-metabolite network and to identify the key active components, targets, and pathways of FZD/ZD in alleviating MASLD.
Molecular docking between FZD/ZD-derived key active compounds and their core targets: The crystal structures of the overlapping targets and the chemical structures of the drug-derived compounds were obtained from the Protein Data Bank (http://www.pdb.org/) and the PubChem database (http://pubchem.ncbi.nlm.nih.gov/), respectively. Water molecules and metal ions were removed from the protein using PyMOL software (version 2.5). Subsequently, AutoDockTools (version 1.5.7) was employed to add hydrogens to the proteins. AutoDock Vina was utilized to dock core proteins with the drug-derived compounds and to calculate binding energies, with a binding energy of < -5 kcal·mol-1, indicating a strong binding affinity.
HepG2 cells were purchased from the Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Beijing, China). were cultured in DMEM supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin at 37 °C in a 5% CO2 incubator. At the logarithmic growth phase, the cells were exposed to 1 mmol/L free fatty acid (FFA; oleic acid-palmitic acid = 2:1) for 24 hours to induce steatosis. The HepG2 cells were then treated with 5 μg/mL and 20 μg/mL of the following key compound groups: The key active compound ensemble of FZD (FZDC), the key active compound ensemble of ZD (ZDC), the key active compound ensemble of FZD comprising only PR compounds (PRC), and the key active compound ensemble of ZD compounds (WOC). The concentration ratios were determined according to the chromatographic peak area ratios of FZD/ZD-derived components in serum. The specific proportions are detailed in the Supplementary Table 1. FC (150 μM) was used as the positive control, and each group was treated for 24 hours. After treatment, lipid accumulation in the cells was observed using oil red O staining, and intracellular levels of TC, TG, ALT, AST, IL-1β, IL-6, and TNF-α were measured. The levels of core targets [aldo-keto reductase family 1 member B (AKR1B1), aldo-keto reductase family 1 member B (AKR1B10), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB)] in HepG2 cells and rat liver tissues were also determined according to the kit instructions.
All statistical analyses were conducted using GraphPad Prism 9.0 (GraphPad Software, CA, United States). Data are presented as mean ± SD. Comparisons among multiple groups were performed using one-way ANOVA. A P-value < 0.05 was considered statistically significant.
No rat mortality was observed and dietary intake remained normal throughout the study. Body weight of rats in all groups increased over 12 weeks, with a significant increase in the HFD group compared to the NC group. Treatment with FZD and FFZD significantly reduced body weight compared to the HFD group (P < 0.01, P < 0.001), whereas ZD treatment showed no significant effects (Figure 1A). No significant differences in food intake were observed (Figure 1B), indicating that the weight reduction was mediated by FZD and FFZD treatments rather than appetite suppression. Liver weight and index values were significantly elevated in the HFD group (P < 0.0001). FZD and FFZD treatments significantly reduced liver index values (P < 0.01, P < 0.001), whereas ZD treatment showed no significant effect compared to the HFD group. No significant differences were observed between the effects of FFZD and FZD on liver index values (Figure 1C and D).
Twelve weeks of HFD feeding successfully induced dyslipidemia and liver injury. FZD treatment significantly decreased serum levels of TC, TG, LDL-C, AST, ALT, and IL-6 (P < 0.05, P < 0.01, P < 0.001, and P < 0.0001) and increased serum HDL-C levels (P < 0.05). FZD treatment also significantly decreased hepatic levels of TC, TG, AST, ALT, and IL-6, and increased hepatic SOD levels (P < 0.05, P < 0.01, P < 0.001, and P < 0.0001). Treatment with ZD significantly reduced serum levels of IL-6, as well as hepatic levels of TC, TG, and AST. Moreover, treatment with FFZD significantly decreased serum levels of TC, TG, ALT, AST, LDL-C, TNF-α, and IL-6 (P < 0.05, P < 0.01, P < 0.001, and P < 0.0001), while significantly increasing serum HDL-C levels (P < 0.01 and P < 0.001). FFZD also significantly reduced hepatic levels of TC, TG, ALT, AST, LDL-C, IL-1β, IL-6, and malondialdehyde (P < 0.05, P < 0.01, P < 0.001, and P < 0.0001), and increased hepatic levels of HDL-C and SOD (P < 0.05, P < 0.01, and P < 0.001; Figure 1E-T).
Hematoxylin and eosin staining revealed severe hepatic steatosis and fat vacuolation in the HFD group. These pathological changes were markedly ameliorated in the FZD and FFZD groups, but not in the ZD group (Figure 1U). Oil red O staining confirmed significant lipid deposition in HFD rats, which was substantially reduced by FZD and FFZD treatment but was not significantly affected by ZD treatment (Figure 1V). Masson’s trichrome staining indicated liver fibrosis in the HFD group, which was reduced to varying degrees by FZD, ZD, and FFZD treatments (Figure 1W).
These results demonstrate that FZD effectively regulates lipid metabolism and improves liver function in MASLD rats, which is diminished upon PR removal. FFZD exhibited superior anti-inflammatory and antioxidant stress effects compared to FZD.
OPLS-DA score plots of serum, liver, urine, and fecal samples showed clear separation between the NC and HFD groups, indicating a distinct metabolic perturbation induced by HFD feeding. The treatment groups were also separated from the HFD group, demonstrating significant interventions on the endogenous metabolome by FZD, FFZD, ZD, and FC (Figure 2). Additionally, a random permutation test (200 times) was performed on the OPLS-DA model. The intercept of the Q2 regression line with the Y-axis was significantly less than zero, indicating that the model was robust and not overfitted. Model parameters demonstrated that R2Y was close to 1 and Q2 < 0 (Supplementary Table 2), further confirming the robustness and predictability of the model.
Differential metabolites were identified using the criteria of variable importance in projection > 1.0 and P < 0.05. After FZD treatment, the levels of 369 differential metabolites in MASLD rats were reversed, including 38, 41, 136, and 154 metabolites in serum, liver, urine, and feces (Supplementary Table 3). ZD regulated 336 differential metabolites, including 32, 65, 119, and 120 metabolites in serum, liver, urine, and feces (Supplementary Table 4). Among them, 148 metabolites were exclusively regulated by FZD (Supplementary Table 5). Pathway enrichment analysis (impact > 0.1 or P < 0.05) revealed that FZD influenced 13 metabolic pathways, while ZD influenced 11 pathways. Five pathways were specifically regulated by FZD, including biotin, ascorbate, aldarate, alanine, aspartate, glutamate, inositol phosphate, and galactose metabolism (Table 1). These specifically regulated pathways may contribute to the enhanced therapeutic efficacy of FZD.
| No | Pathway name | Match status | Compound |
| 1 | Biotin metabolism1 | 1/10 | FZD |
| 2 | Riboflavin metabolism | 1/4 | FZD/ZD |
| 3 | Ascorbate and aldarate metabolism1 | 1/9 | FZD |
| 4 | Starch and sucrose metabolism | 1/18 | FZD/ZD |
| 5 | Alanine, aspartate and glutamate metabolism1 | 1/28 | FZD |
| 6 | Inositol phosphate metabolism1 | 2/30 | FZD |
| 7 | Galactose metabolism1 | 2/27 | FZD |
| 8 | Primary bile acid biosynthesis | 2/39 | FZD/ZD |
| 9 | Pyrimidine metabolism | 2/32 | FZD/ZD |
| 10 | Glyoxylate and dicarboxylate metabolism | 2/30 | FZD/ZD |
| 11 | Lysine degradation | 2/30 | FZD/ZD |
| 12 | Arginine and proline metabolism | 2/36 | FZD/ZD |
| 13 | Neomycin, kanamycin and gentamicin biosynthesis | 1/20 | FZD/ZD |
| 14 | Arginine biosynthesis | 1/14 | ZD |
| 15 | Porphyrin metabolism | 1/36 | ZD |
| 16 | Arachidonic acid metabolism | 2/44 | ZD |
A total of 39, 38, and 29 drug-derived compounds were identified in serum of MASLD rats treated with FZD, FFZD, and ZD, respectively (Table 2). Ten compounds in FZD were absent in ZD, six of which were derived from PR, including dehydrotrametenolic acid, poroic acid A, 16α-hydroxydehydrotrametenolic acid, dehydropachymic acid, 3-epi-dehydrotubulosic acid derivative, and 16α-acetoxypolyporenic acid C glucoside.
| No. | tR (minutes) | ESI-MSn(+) [m/z (abundance)] | [M-H]-, (m/z) | ESI-MSn(-) [m/z (abundance)] | Predicted formula | Predicted (m/z) | Meas (m/z) | Difference (ppm) | Assigned identification | Source | HFZD | HZD | HFFZD | |
| 1 | 7.622 | 453.3365 | 435.3339, 339.2764 | C30H44O3 | 453.3363 | 453.3365 | 0.44 | Dehydrotrametenonlic acid | PR | + | - | + | ||
| 2 | 26.574 | 469.3311 | 349.7395, 174.9792 | C30H44O4 | 469.3311 | 469.3312 | 0.21 | glabriolactone | GR | + | - | + | ||
| 3 | 24.157 | 499.3466 | 425.1423, 327.0222 | C31H46O5 | 499.3418 | 499.3466 | 9.61 | Poricoic acid A | PR | + | - | + | ||
| 4 | 26.678 | 469.3323 | 407.2804 | C30H46O4 | 469.3323 | 469.3323 | 0 | 16α-hydroxydehydrotrametenolic acid | PR | + | - | + | ||
| 5 | 26.640 | 527.3782 | 509.3213, 449.8736, 353.0937, 393.1475 | C33H50O5 | 527.3731 | 527.3782 | 9.67 | Dehydropachymic acid | PR | + | - | + | ||
| 6 | 7.351 | 487.3470 | 453.3328, 435.3235, 381.2900 | C30H48O5 | 487.3429 | 487.3470 | 8.41 | Alisol F | AR | + | + | + | ||
| 7 | 26.464 | 627.3900 | 567.2529, 483.0927, 479.1345 | C37H56O8 | 627.3902 | 627.3900 | -0.32 | 3−epi−(3′−hydroxyl−3′−methylglutaryloxyl)−dehydrotumulosic acid | PR | + | - | - | ||
| 8 | 17.095 | 525.3550 | 310.0712 | C33H48O5 | 525.3575 | 525.3550 | -4.76 | 16α-acetoxypolyporenic acid C | PR | + | - | + | ||
| 9 | 7.285 | 475.3746 | 457.3129 | C30H50O4 | 475.3782 | 475.3746 | -7.58 | 11-deoxyalisol A | AR | + | + | + | ||
| 10 | 7.392 | 609.3092 | 353.0858 | C32H48O9S | 609.3092 | 609.3092 | 0 | Alisol-23acetate-11-o-sul | AR | + | + | + | ||
| 11 | 8.474 | 255.0663 | 135.0869, 119.0558 | C15H12O4 | 255.0663 | 255.0663 | 0 | Liquiritigenin | GR | + | + | + | ||
| 12 | 27.213 | 469.3323 | 451.5547, 187.9521 | C30H46O4 | 471.3469 | 471.3474 | 1.06 | Glycyrrhetinic acid | GR | + | + | + | ||
| 13 | 5.754 | 433.1130 | 257.0802, 239.0708, 137.0234 | C21H20O10 | 433.1129 | 433.1134 | 1.15 | vitexin | GR | + | + | + | ||
| 14 | 9.438 | 417.1191 | 255.0645, 135.0453, 119.0500 | C21H22O9 | 417.1191 | 417.1191 | 0 | liquiritin | GR | + | + | + | ||
| 15 | 14.050 | 355.1177 [M+Na]+ | 299.0539 | C18H20O6 | 355.1176 | 355.1177 | 0.28 | licoflavonol | GR | + | + | + | ||
| 16 | 15.597 | 353.1019 | 311.0551, 255.2080 | C20H16O6 | 353.1020 | 353.1019 | 0.28 | Licorice isoflavone B | GR | + | + | + | ||
| 17 | 6.021 | 393.2098 | 337.2133 | C25H28O4 | 393.2060 | 393.2098 | 9.67 | Glabrol | GR | + | + | + | ||
| 18 | 13.778 | 407.1824 | 309.2223, 203.1442 | C25H28O5 | 407.1846 | 407.1824 | -5.40 | 6, 8-isoprene naringenin | GR | + | + | + | ||
| 19 | 12.997 | 347.2216 | 177.0909, 137.0964 | C21H30O4 | 347.2217 | 347.2216 | -0.29 | 1-Dehydro-[10]-gingerdione | ZR | + | + | + | ||
| 20 | 12.262 | 393.2623 | 357.2356, 179.0707, 163.0622, 153.1278 | C23H36O5 | 393.2636 | 393.2623 | -3.30 | Acetoxy-10-gingerol | ZR | + | + | + | ||
| 21 | 5.700 | 249.1481 | 179.0524, 137.0505 | C15H20O3 | 249.1485 | 249.1481 | -1.61 | 4-Shogaol | ZR | + | - | + | ||
| 22 | 36.479 | 349.2360 | C21H34O4 | 349.2384 | 349.2360 | -6.87 | (10)-Gingerol | ZR | + | - | + | |||
| 23 | 7.978 | 357.1667 | 301.2139, 221.1555 | C21H24O5 | 357.1697 | 357.1667 | Gingerenone A | ZR | + | + | + | |||
| 24 | 4.730 | 147.0452 | 132.0899, 102.9460 | C9H8O2 | 147.0452 | 149.0452 | Cinnamic acid | CR | + | + | + | |||
| 25 | 4.355 | 167.0352 | 167.0228, 123.0091 | C8H8O4 | 167.035 | 167.0352 | Vanillic acid | CR | + | + | + | |||
| 26 | 12.439 | 133.0648 | 115.0531, 105.0704 | C9H8O | 133.0648 | 133.0648 | Cinnamaldehyde | CR | + | + | + | |||
| 27 | 6.503 | 135.0804 | 117.0702 | C9H10O | 135.0804 | 135.0804 | cinnamyl alcohol | CR | + | + | + | |||
| 28 | 12.439 | 161.0598 | 143.0731, 146.0357 | C10H8O2 | 161.0597 | 161.0598 | 6-methylcoumarin | CR | + | + | + | |||
| 29 | 2.168 | 165.0546 | 147.0580, 119.2572 | C9H8O3 | 165.0546 | 165.0546 | Hydroxycinnamic acid | CR | + | + | + | |||
| 30 | 1.517 | 227.1074 | 209.9436, 181.0748, 125.1080 | C15H14O2 | 227.1067 | 227.1074 | Phenethyl benzoate | CR | + | + | + | |||
| 31 | 13.749 | 429.1731 | 295.2434, 163.1116 | C20H28O10 | 429.1755 | 429.1731 | Cinnamylalcohol-6’-o-α-furanara-binose-O-β-glucopyranoside | CR | + | + | + | |||
| 32 | 5.700 | 249.1481 | 214.0802 | C15H20O3 | 249.1485 | 249.1481 | Leucocarcinolide III | AMR | + | - | + | |||
| 33 | 10.027 | 161.0242 | 133.5619, 105.0430 | C9H6O3 | 163.039 | 163.0393 | 7-hydroxycoumarin | AMR | + | + | + | |||
| 34 | 1.179 | 191.1077 | 107.0470 | C12H14O2 | 191.1067 | 191.1077 | Ligustilide | AMR | + | + | + | |||
| 35 | 4.362 | 118.0862 | 118.0634 | C5H11NO2 | 118.0863 | 118.0862 | Betaine | AMR | + | + | + | |||
| 36 | 3.666 | 355.1008 | 163.1118, 145.1012 | C16H18O9 | 355.1029 | 355.1008 | Chlorogenic acid | AMR | + | + | + | |||
| 37 | 20.095 | 281.1394 | 281.2495, 263.2373 | C15H22O5 | 281.1394 | 281.1394 | 4,6-dihydroxy-3,3a-dihydroatractylenolide III | AMR | + | + | + | |||
| 38 | 17.244 | 415.3201 | 157.0638, 129.1023, 105.0374 | C27H42O3 | 415.3207 | 415.3201 | Diosgenin | AMR | + | + | + | |||
| 39 | 19.881 | 431.2206 | 269.0800, 152.9978 | C21H36O9 | 431.2287 | 431.2206 | Dictamnoside A | AMR | + | + | + |
Next, the targets of these FZD-derived and ZD-derived compounds against MASLD were identified. A total of 498 and 444 potential anti-MASLD targets were predicted for FZD and ZD compounds, respectively, using network pharmacology. In addition, 404 and 406 metabolic pathway-related targets were obtained from the 13 FZD-regulated and 11 ZD-regulated 11 metabolic pathways, respectively, using the KEGG database. Then, 26 targets were obtained by intersecting the 498 anti-MASLD targets of FZD-derived compounds with the 404 metabolic pathway-related targets using Venny 2.1.0 (Figure 3A). Similarly, 38 targets were obtained by intersecting the 444 anti-MASLD targets of ZD-derived compounds with the 406 metabolic pathway-related targets (Figure 3B). A component-target-metabolic pathway-metabolite network was constructed using Cytoscape. The network showed that these 26 key targets were associated with 22 FZD-derived compounds, 13 metabolic pathways, and 13 metabolites (Figure 3C), and were thereby considered the core targets and key effector components of FZD against MAFLD. which were associated with 17 ZD-derived compounds, 11 metabolic pathways, and 16 metabolites (Figure 3D) and were thereby considered the core target and key effector components of ZD against MAFLD. In comparison, 17 core targets were specifically regulated by FZD, including hydroxyacid oxidase 1, thymidylate synthetase, dihydroorotate dehydrogenase, AKR1B1, AKR1B10, aldo-keto reductase family 1 member A1, glucuronidase beta, glycogen phosphorylase muscle, folate hydrolase 1, aldehyde dehydrogenase 5 family member A1, PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta, phospholipase C gamma 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, PI4KB, phosphatidylinositol 4-kinase beta, and acid phosphatase 1. The component-target-metabolic pathway-metabolite network further indicated that 20 FZD-derived compounds may serve as key active compounds, acting on these 17 core targets, regulating eight key metabolic pathways, and affecting 21 metabolites, thereby contributing to stronger anti-MASLD efficacy compared with ZD (Figure 3E).
Finally, molecular docking between the key active substances and the core targets showed that all binding energies were less than -5.0 kcal/mol (Table 3), suggesting that the 17 key active compounds derived from FZD exhibited favorable binding ability for their targets (binding sites are shown in Figure 3F).
| No. | Target | Component | Binding energy (kcal/mol) |
| 1 | HAO1 | Dehydrotrametenonic acid | -19.8 |
| 2 | 16α-Hydroxydehydrotrametenolic acid | -18.9 | |
| 3 | Glycyrrhetinic acid | -18.9 | |
| 4 | TYMS | Dehydropachymic acid | -9.1 |
| 5 | DHODH | Dehydrotrametenonic acid | -6.2 |
| 6 | AKR1B1 | Liquiritigenin | -5.6 |
| 7 | Liquiritin | -6.9 | |
| 8 | Chlorogenic acid | -6.5 | |
| 9 | AKR1B10 | Dehydrotrametenonic acid | -7.2 |
| 10 | Glabrolide | -7.3 | |
| 11 | Poricoic acid A | -5.8 | |
| 12 | 16α-hydroxydehydrotrametenolic acid | -6.8 | |
| 13 | Glycyrrhetinic acid | -6.7 | |
| 14 | Chlorogenic acid | -6.3 | |
| 15 | AKR1A1 | Glabrol | -8.9 |
| 16 | GUSB | 4-shogaol | -6.9 |
| 17 | PYGM | Glabrolide | -9 |
| 18 | ALDH5A1 | 7-hydroxycoumarin | -6.4 |
| 19 | PIK3CA | Alisol F | -7.1 |
| 20 | Liquiritigenin | -5.8 | |
| 21 | PIK3CD | Alisol F | -9.2 |
| 22 | Glabrol | -7.8 | |
| 23 | 4-Shogaol | -7 | |
| 24 | (10)-Gingerol | -6.5 | |
| 25 | Gingerenone A | -7.1 | |
| 26 | Ligustilide | -6.9 | |
| 27 | Phenethyl benzoate | -7 | |
| 28 | PLCG1 | Dehydropachymic acid | -7.2 |
| 29 | 1-Dehydro-[10]-gingerdione | -5 | |
| 30 | PIK3CG | Glabrol | -9.1 |
| 31 | 1-Dehydro-[10]-gingerdione | -6.7 | |
| 32 | 4-Shogaol | -7.1 | |
| 33 | Gingerenone A | -7.8 | |
| 34 | PIK3CB | Alisol F | -9.5 |
| 35 | Liquiritigenin | -7.5 | |
| 36 | 4-Shogaol | -6 | |
| 37 | (10)-Gingerol | -5.3 | |
| 38 | Gingerenone A | -6.4 | |
| 39 | PI4KB | 4-Shogaol | -6.3 |
| 40 | ACP1 | Poricoic acid A | -7.7 |
| 41 | 16α-hydroxydehydrotrametenolic acid | -7.6 |
The anti-MASLD activity of the key effector compound group, including FZDC, ZDC, PRC, and WOC, was evaluated in FFA-induced HepG2 cells. Oil red O staining demonstrated that FFA treatment induced lipid accumulation in HepG2 cells, whereas treatment with FZDC and PRC significantly reduced intracellular lipid droplet accumulation (P < 0.001 and P < 0.0001), while ZDC showed only a mild effect at low dose, and WOC was ineffective (Figure 4A and B). Additionally, FZDC significantly decreased intracellular TC, TG, ALT, and AST levels (P < 0.05, P < 0.01, and P < 0.001). PRC significantly reduced TC and AST levels, whereas WOC reduced ALT and AST levels. ZDC treatment showed no significant improvement (Figure 4C-F). Overall, FZDC and PRC ameliorated FFA-induced lipid accumulation in HepG2 cells, thereby alleviating steatosis, while ZDC and WOC showed relatively weak effects on steatosis, indicating that the PR compounds in the key active substances of FZD are indispensable for MASLD prevention.
FZDC and PRC significantly increased the levels of the core targets PIK3CA and AKR1B10 in HepG2 cells (P < 0.05 and P < 0.01), whereas ZDC and WOC did not (Figure 4G and H). In addition, the expression levels of PIK3CA, PIK3CB, AKR1B1, and AKR1B10 in the rat liver tissues were significantly increased after treatment with FZD (P < 0.05 and P < 0.01), whereas ZD had no significant effect (Figure 4I-L). These results suggest that the key effector compounds of FZD improved hepatocellular steatosis by regulating the expression of PIK3CA and AKR1B10.
Traditional Chinese medicine often employs formulations to treat complex diseases such as MASLD by systematically regulating the overall physiological state of the organism. FZD, a classical prescription in which PR serves as the “sovereign drug”, has demonstrated clinical efficacy in managing glucolipid metabolic disorders. In traditional Chinese medicine theory, the sovereign drug is considered the primary agent responsible for addressing the main disease or syndrome. However, the yield of PR in aqueous extractions is only approximately 3% and is not increased after compatibility with other herbs in FZD. Thus, the pharmacodynamic contribution of PR, its mechanisms, and other active constituents within FZD remain to be further explored.
This study systematically deconstructed the FZD prescription to clarify the role of PR. We found that although FZD, FFZD (with PR dregs), and ZD (without PR) all ameliorated liver pathology and lipid metabolism, the effect of ZD was markedly weaker. The addition of PR dregs enhanced the formula’s anti-oxidative stress and anti-inflammatory activities. These findings demonstrate that PR serves as the important component responsible for the therapeutic efficacy of FZD against MASLD. Since approximately 70%-90% of PR is primarily waterinsoluble polysaccharides, traditional decoction methods utilize only its water-soluble constituents, which represent a small fraction of PR. In this study, the extraction dregs of PR were recovered and coadministered with FZD in rats to explore the waterinsoluble polysaccharides of PR. We found that FFZD exhibited lipidregulating effects comparable to those of FZD, while demonstrating superior antioxidant and antiinflammatory activities. These results suggest that the water-insoluble polysaccharides of PR may constitute the key active components responsible for its efficacy; however, their bioavailability and underlying mechanisms require further investigation. Based on these findings, we propose that PR should be decocted in a powdered form using filter bags, and that the resulting PR dregs should be retained and consumed together with the decoction to enhance therapeutic efficacy.
We subsequently conducted metabolomic analyses of serum, liver, urine, and fecal samples. Differential metabolite analysis revealed that FZD significantly regulated 369 metabolites, while ZD modulated 336 metabolites. FZD specifically altered 148 metabolites. The pathway enrichment analysis identified 13 and 11 significantly enriched metabolic pathways for FZD and ZD, respectively. Notably, FZD specifically regulated five pathways: Biotin, ascorbate, aldarate, alanine, aspartate, glutamate, inositol phosphate, and galactose metabolism. Among these pathways, galactose is not only an energy source but also a structural molecule essential for human development and physiological function. It is a key component of complex macromolecules such as glycoproteins, glycolipids, and proteoglycans. Glycosylation, one of the core functions of galactose, participates in cell growth, differentiation, migration, morphogenesis, and cell-to-cell interactions. Galactose is also a crucial constituent of galactocerebroside, a major glycolipid in myelin, and is essential for nervous system development. Its metabolic pathway is highly conserved, and metabolic disorders of galactose can lead to severe diseases, while also providing new therapeutic insights[11]. The ascorbate and aldarate metabolism pathway are an important carbohydrate metabolic pathway involved in protecting cells from oxidative damage[12]. Among the metabolites involved in these pathways, myo-inositol, which participates in lipid signaling, glucose, and insulin metabolism, has been found to effectively ameliorate endocrine diseases such as diabetes and insulin resistance[13]. Meanwhile, emerging evidence shows that L-glutamine plays a fundamental role in cardiovascular physiology and pathology, exerting antioxidant and anti-inflammatory effects by inducing heme oxygenase-1, heat shock proteins, and glutathione[14,15]. Similarly, uridine, a pyrimidine nucleoside derived from plants or animals, can effectively reduce the accumulation of collagen and downregulate the expression of α-smooth muscle actin, collagen type I, and fibronectin in the liver. Consequently, it was shown to improve hepatocyte activity and alleviate CCl4-induced liver injury and fibrosis[16]. These findings suggest that these specialized regulatory pathways and metabolites may contribute to the superior efficacy of FZD.
Next, we performed an analysis of drug-derived components in the blood. A total of 39 and 29 components were identified in the FZD and ZD groups, respectively. FZD exhibited 10 additional drug-derived components in the blood than ZD, namely dehydrotrametenolic acid, poricoic acid A, 16α-hydroxydehydrotrametenolic acid, dehydropachymic acid, 3-epi-(3’-hydroxy-3’-methylglutaryloxy)-dehydrotumulosic acid, 16α-acetoxypolyporenic acid C, glabrolide, 4-shogaol; (10)-gingerol, and leucocarcinolide III, six of which were derived from PR. Among them, dehydrotrametenolic acid functions as an insulin sensitizer and alleviates nonalcoholic steatohepatitis by targeting caspase-1 and modulating macrophage-hepatocyte/hepatic stellate cell crosstalk, thereby suppressing nod-like receptor protein 3 inflammasome activation[17]. Poricoic acid A has been reported to regulate inflammatory responses, attenuate oxidative stress, modulate apoptosis, and inhibit fibrosis, thereby exerting protective effects in various diseases such as gestational diabetes mellitus[18-20]. The other components have not been associated with MASLD-related symptoms and thus warrant further investigation.
The intersection between targets enriched in metabolic pathways and targets of drug-derived components against MASLD predicted by network pharmacology was further analyzed. For FZD, 26 common targets corresponding to 22 drug-derived components were obtained, while for ZD, 38 common targets corresponding to 17 drug-derived components were obtained. These components may represent key effector components of FZD and ZD against MASLD. The results indicate that FZD has more active components than ZD (six of which are derived from PR), and FZD specifically regulates 17 additional targets. Component-target-pathway-metabolite association analysis revealed that a total of 20 active components in FZD act on these 17 specific targets. These 20 active components are likely the material basis for the stronger efficacy of FZD.
Finally, in vitro validation using the reconstituted key bioactive component ensembles confirmed that FZDC exhibited superior efficacy compared to ZDC, WOC, and PRC. The enhanced activity of FZDC was primarily reflected in the significant decrease in intracellular lipid accumulation; decreased levels of TC, TG, ALT, and AST; lower concentrations of IL-1β, IL-6, and TNF-α; and the modulation of key targets such as PIK3CA and AKR1B10. PRC also demonstrated moderate therapeutic effects, mainly by alleviating cellular lipid deposition, reducing pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and regulating the expression of PIK3CA and AKR1B10.
Furthermore, both FZD and FFZD significantly regulated the expression of key proteins PIK3CA and AKR1B10. Similarly, FZDC also effectively modulated the expression of these targets, whereas neither ZDC nor WOC demonstrated a significant regulatory effect on either protein. These results confirm the indispensable role of PR in the complete formula for treating MASLD. Incorporating PR not only enhances the bioavailability and activity of its own bioactive constituents but also modifies the pharmacokinetic profile of other herbal components. This synergistic interaction promotes the release and action of a broader spectrum of active constituents from other herbs, collectively enhancing therapeutic efficacy against MASLD.
The limitations of this research: The present study has several limitations, primarily related to the pharmacodynamic material basis, validation of key targets, and formulation quality control. First, the pharmacodynamic material basis remains incompletely elucidated. Specifically, the in vivo absorption, distribution, metabolism, and excretion of the abundant water-insoluble polysaccharides from PR remain unclear. Although these polysaccharides may exert indirect pharmacological effects through gut microbiota fermentation, their specific contribution and in vivo fate require further investigation. Second, although core targets such as hydroxyacid oxidase 1, AKR1B1, and thymidylate synthetase were identified through network pharmacology and their expression changes were validated by enzyme-linked immunosorbent assay, in vivo causal validation using gene knockout models or specific inhibitors was not performed. In addition, molecular docking provides only theoretical predictions, and docking scores have inherent limitations; therefore, further biological experiments are required to verify the actual binding effects. Finally, regarding formulation quality control, only atractylenolide II was quantified in this study, while the characteristic triterpenes of PR (e.g., dehydrotrametenolic acid, poricoic acid A) were not included as quality markers, which, to some extent, compromises the controllability and batch-to-batch consistency of the formulation. Despite these limitations, this study reveals, for the first time, the important role of PR as the sovereign herb in FZD and provides a foundation for future research. Further studies should further investigate the pharmacokinetic profiles of the polysaccharide components, employ target-intervention models to validate relationships, and establish quality control standards for PR triterpenes.
As the key medicinal component in FZD, PR plays an irreplaceable role in FZD treatment for MASLD. Removing PR significantly weakened the therapeutic effect of FZD on MASLD. The superior efficacy of FZD against MASLD is primarily attributed to the presence of more diverse and distinctive active components (six of which originate from PR), along with its specific regulation of five metabolic pathways (biotin, ascorbate, aldarate, alanine, aspartate, glutamate, inositol phosphate, and galactose metabolism) and 148 differential metabolites. Incorporating PR dregs enhanced the antioxidant and anti-inflammatory activities of FZD, suggesting that the substantial number of water-insoluble polysaccharides in dregs is the key bioactive constituent responsible for the observed therapeutic effects.
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