Search Results (565)

Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1a), and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) are promising treatments for chronic kidney disease. This umbrella review of network meta-analyses evaluated their effects on cardiovascular outcomes, kidney disease progression, and adverse events, using the TOPSIS method to identify the optimal intervention based on P-scores. A total of 19 network meta-analyses and 44 randomized controlled trials involving 86,150 chronic kidney disease patients were included. Compared to placebo, SGLT2i were associated with reduced risks of cardiovascular events [Hazard ratio (HR): 0.776, 95% confidence intervals (CI): 0.727–0.998], kidney disease progression (HR: 0.679, 95% CI: 0.629–0.733), acute kidney injury (HR: 0.873, 95% CI: 0.773–0.907), and serious adverse events (HR: 0.881, 95% CI: 0.847–0.916). GLP1a and ns-MRA were also associated with significant reductions in cardiovascular and kidney-specific composite outcomes. Indirect evidence showed that SGLT2i demonstrated a lower risk of kidney disease progression compared to GLP1a (HR: 0.826, 95% CI: 0.716–0.952) and ns-MRA (HR: 0.818, 95% CI: 0.673–0.995), representing the best intervention across all endpoints. In conclusion, while SGLT2i, GLP1a, and ns-MRA all reduce cardiovascular and kidney disease risks in chronic kidney disease, SGLT2i appears to provide the most favorable balance of efficacy and safety. Full article

Background: Alpiniae oxyphyllae Fructus (AOF) is a medicinal and edible resource that holds potential to ameliorate hyperuricemia (HUA), yet its mechanism of action warrants further investigation. Methods: We performed network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experiments to investigate the potential action and mechanism of AOF against HUA. Results: The results indicate that 48 potential anti-HUA targets for 4 components derived from AOF were excavated and predicted through public databases. Gene Ontology (GO) enrichment analysis indicated that there are 190 entries related to biological process, 24 entries related to cellular component, 42 entries related to molecular function, and 44 entries related to Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. The results of molecular docking showed that the main active ingredients of AOF may have potential therapeutic effects on immune system disorders and inflammation caused by HUA by binding to targets including peroxisome-proliferator-activated receptor gamma (PPARG), estrogen receptor 1 (ESR1), prostaglandin G/H synthase 2 (PTGS2), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Subsequently, we further determined the stability of the complex between the core active ingredient and the core target proteins by molecular dynamics simulation. The results of cell experiments demonstrated that stigmasterol as the core active ingredient derived from AOF significantly upregulated the expression levels of ESR1 and PPARG (p < 0.001) to exert an anti-HUA effect. Conclusions: In summary, we have systematically elucidated that the mechanism of main active ingredients derived from AOF mainly exert their pharmacological effects by acting on multiple targets in this study. Our studies will provide a scientific basis for the precise development and utilization of AOF. Full article

Asthma is a chronic inflammatory respiratory disease that affects millions globally and poses a serious public health challenge. Current therapeutic strategies, including corticosteroids, are constrained by variable patient responses and adverse effects. In this study, a polyphenolic extract derived from the Tibetan medicinal plant Spenceria ramalana Trimen (SRT) was employed and shown to improve experimentally (ovalbumin + cigarette smoke, OVA + CS) induced asthma in rats. Initially, the potential therapeutic mechanism of the polyphenolic components in SRT on OVA + CS-induced asthma was predicated by network pharmacology analysis. Subsequently, in vivo experiments identified that SRT polyphenols exhibit significant anti-asthmatic activities, primarily mediated by lowering inflammatory cell counts such as the WBC (white blood cell), eosinophils, and neutrophils, decreasing the expression of inflammatory cytokines (IL-4, IL-5, IL-13, and TNF-α), alleviating lung histological damage (reduced inflammation, collagen deposition, and mucus secretion), and enhancing the epithelial barrier integrity (upregulation of ZO-1, occludin, and claudin-1). Additionally, SRT polyphenols downregulated the PI3K/Akt (Phosphoinositide 3-kinase/protein kinase B) signaling pathway, improved gut microbiota disruption, and regulated fecal metabolites (glucose-6-glutamate, PS (16:0/0:0), 8-aminocaprylic acid, galactonic acid, Ascr#10, 2,3,4,5,6,7-hexahydroxyheptanoic acid, phosphodimethylethanolamine, muramic acid, 9-oxohexadeca-10e-enoic acid, and sedoheptulose) in asthmatic rats. In conclusion, SRT polyphenols exerted multifaceted protective effects against OVA + CS-induced asthma in rats, highlighting their potential value in preventing asthma via the PI3K/Akt signaling pathway. Full article

Background: Gegen Qinlian Decoction (GQD), is used for intestinal disorders like ulcerative colitis, irritable bowel syndrome, and colorectal cancer. But the precise mechanisms underlying its anti-inflammatory and anti-tumor effects are not fully elucidated. Methods: Use network pharmacology to identify targets and pathways of GQD. In vivo (azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colorectal cancer (CAC) mouse model) and in vitro (lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages) experiments were conducted to explore GQD’s anti-inflammatory and anti-tumor effects. We monitored mouse body weight and disease activity index (DAI), and evaluated colon cancer tissues using hematoxylin and eosin staining. Expression of Ki67 and F4/80 was determined by immunohistochemistry analysis. The protein levels of TLR4 signaling pathway were assessed by western blotting analysis. Enzyme-linked immunosorbent assay measured IL-1β, IL-6, and TNF-α levels. Immunofluorescence (IF) staining visualized NF-κB and IRF3 translocation. Results: There were 18, 9, 24 and 77 active ingredients in the four herbs of GQD, respectively, targeting 435, 156, 485 and 691 genes. Through data platform analysis, it was concluded that there were 1104 target genes of GQD and 2022 target genes of CAC. Moreover, there were 99 intersecting genes between GQD and CAC. The core targets of GQD contained NFKB1, IL1B, IL6, TLR4, and TNF, and GQD reduced inflammation by inhibiting the TLR4 signaling pathway. In vivo experiment, GQD increased mouse body weight, lowered DAI scores, while also alleviating histopathological changes in the colon and decreasing the expressions of Ki67 and F4/80 in the AOM/DSS-induced mice. GQD reduced IL-1β, IL-6, and TNF-α levels in the serum and downregulated TLR4, MyD88, and phosphorylation of IκBα, P65, and IRF3 in the colon tissue from AOM/DSS-induced mice. In vitro, GQD suppressed pro-inflammatory cytokines and TLR4 signaling pathway in the LPS-induced RAW264.7 cells, and combined with TAK242, it further reduced the phosphorylation of IκBα, P65. Conclusions: GQD mitigated CAC by inhibiting the TLR4 signaling pathway, offering a potential therapeutic approach for CAC management. Full article

Background: Radix Paeoniae Rubra (RPR), an edible and medicinal Traditional Chinese Medicine (TCM), is extensively employed in therapeutic interventions of cardiovascular and cerebrovascular diseases. However, the curative effect of RPR on ischemic stroke remains ambiguous. This work integrated network pharmacology, molecular docking, and experimental validation to explore the mechanisms of RPR in treating ischemic stroke. Methods: In this study, we preliminarily elucidated the therapeutic effect and mechanism of RPR on ischemic stroke through network pharmacology, molecular docking analysis, and experimental verification. Results: The results indicated that RPR improved the neurological deficit scores, decreased the size of infarcts, and reduced brain edema symptoms in the tMCAO mice model. Furthermore, through network pharmacology and molecular docking, four core targets (MAPK3, TNF-α, MAPK14, and JNK) closely related to RPR’s treatment of ischemic stroke were identified, exhibiting strong affinity with two key active components of RPR: albiflorin (AF) and β-sitosterol (BSS). The Western blot showed the potential mechanism of RPR treatment for ischemic stroke by regulating the MAPK signaling pathway. Moreover, RPR and its main active ingredients exhibited a significant inhibitory effect on platelets. Conclusion: In conclusion, this study revealed that RPR alleviates ischemic injury by activating the MAPK signaling pathway, and its protective effect may partly stem from inhibiting platelet activation. This work may provide a scientific basis for the development and utilization of RPR as a natural edible material to prevent ischemic stroke and anti-platelet therapy. Full article

Jacaranone derived from Senecio scandens, a traditional Chinese medicine used for centuries, has been documented to exhibit anti-inflammatory and antiproliferative properties in various tumor cell lines. However, the mechanism of action and relationship between inflammation and apoptosis induced by jacaranone remain inadequately elucidated. In this study, the targets of jacaranone and cancer were identified from various databases, while potential targets and pathways were predicted through the analysis of the protein–protein interactions (PPI) network and pathway enrichment. Through a comprehensive network pharmacology analysis and corroborating experimental findings, we revealed that jacaranone induces tumor cell death by fine-tuning the tumor necrosis factor receptor 1 (TNFR1) downstream signaling pathway. TNFR1 serves as a key node that assembles into complexes I and II, regulating pathways including the nuclear factor (NF)-κB signaling pathway and the cell apoptosis pathway, which play crucial roles in cellular life activities. Jacaranone successfully guides survival signaling pathways to apoptotic mechanisms by inhibiting the assembly of complex I and promoting the formation of complex II. In particular, the main action mechanism of jacaranone lies in inducing the degradation of the inhibitor of apoptosis protein (cIAP)-2. cIAP-2 serves as an E3 ubiquitin ligase that ubiquitinates receptor-interacting serine/threonine-protein kinase 1 (RIPK1), thereby hindering the formation of complex I and effectively reducing the phosphorylation of Inhibitor of κB kinase (IKK) β. When the deubiquitylation process of RIPK1 is triggered, it may promote the formation of complex II, which ultimately leads to cell apoptosis. This fully demonstrates the key role of jacaranone in regulating TNFR1 complexes, especially through the degradation of cIAP-2. Taken together, jacaranone hinders the assembly of TNFR1 complex I and promotes the formation of complex II to induce apoptosis of cancer cells. Our findings unveil a novel mechanism underlying jacaranone, while also presenting a fresh approach for the development of new pharmaceuticals. Full article

The luteolin in Schisandra chinensis [Schisandraceae Schisandra (Turcz.) Baill.] were extracted by ultrasonic extraction assisted by an ionic liquid–enzyme composite system, and the content of luteolins was determined using high-performance liquid chromatography (HPLC). This process was initially conducted through a one-factor experiment and a Box–Behnken combinatorial design of response surface method. The extraction process was optimized, and the results demonstrated that the optimal extraction conditions were 13.31% enzyme addition, 0.53 mol/L ionic liquid concentration, 173.47 min ultrasonic shaking, and 0.2266 mg/g, which was 4.88 times higher than that of the traditional reflux extraction. Secondly, the antioxidant function of luteolins was studied based on network pharmacology. For the study of the antioxidant mechanism of luteolin, the herb group identification database, SwissTargetPrediction on luteolins target prediction, and GeneCards database to achieve the antioxidant target were used. For the analysis of the intersection of the target protein interactions, GO bioanalysis and KEGG signaling pathway enrichment analysis were used. There were 57 overlapping targets of luteolin and antioxidants, including AKT1, MMP9, ESR1, EGFR, and SRC. GO function and KEGG pathway enrichment analysis showed that luteolin antioxidants were related to zoerythromycin metabolic process, adriamycin metabolic process, negative regulation of apoptotic process, endocrine resistance and oxidoreductase. The key targets in the pathways, such as luteolin AKT1 and MMP9, exert antioxidant effects. The antioxidant activity of luteolins was investigated by determining the scavenging ability of luteolins against two types of free radicals: 2,2-bipyridine-bis(3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt (ABTS+) free radicals and 1,1-diphenyl-2-trinitrophenylhydrazine free radicals (DPPH-). The results of the antioxidant test demonstrated that the ABTS radical scavenging rate was 87.26%, and the DPPH radical scavenging rate was 93.85% when the quality concentration of Schisandra luteolins was 0.1 mg/g, indicating the potential of this natural antioxidant. This method of extracting Schisandra chinensis luteolins is highly productive, environmentally friendly, and practical, and it facilitates the development and utilization of industrial Schisandra chinensis. Full article

Flavonoids derived from plants in the citrus family can have an alleviating effect on allergic asthma. The aim of this study was to provide insights into the mechanisms by which these compounds exert their effects on allergic asthma by combining theoretical and practical approaches. Aurantii Fructus Immaturus flavonoids (AFIFs) were obtained by solvent extraction and were determined by high performance liquid chromatography (HPLC). In vivo and in vitro experiments combined with network pharmacology, Mendelian randomization (MR) analysis and the AutoDock method were applied to study the mechanism of their effects. The main AFIFs were found to be hesperidin (13.21 mg/g), neohesperidin (287.26 mg/g), naringin (322.56 mg/g), and narirutin (19.35 mg/g). Based on the network pharmacology and MR analysis results, five targets Caspase 3 (CASP3), CyclinD1 (CCND1), Intercellular adhesion molecule (ICAM), erb-b2 receptor tyrosine kinase 2 (ERBB2), and rubisco accumulation factor 1 (RAF1) were selected, and the interactions between the AFIFs and the targets were studied using AutoDock Vina. The results indicated that glycosidic bonds play an important role in the interactions between AFIFs and both ERBB2 and RAF1. Full article

Background: Hepatocellular carcinoma (HCC), a prevalent form of primary liver malignancy, arises from liver-specific hepatocytes. Senecio scandens Buch.-Ham(Climbing senecio) is a bitter-tasting plant of the Compositae family with anti-tumor properties. This study aims to identify the molecular targets and pathways through which Climbing senecio regulates HCC. Methods: Active ingredients of Climbing senecio were collected from four online databases and mapped to relevant target databases to obtain predicted targets. After recognizing the key pathways through which Climbing senecio acts in HCC. Gene expression data from GSE54238 Underwent differential expression and weighted gene correlation network analyses to identify HCC-related genes. The “Climbing senecio-Hepatocellular Carcinoma Targets” network was constructed using Cytoscape 3.10.1 software, followed by topology analysis to identify core genes. The expression and distribution of key targets were evaluated, and the differential expression of each key target between normal and diseased samples was calculated. Moreover, single-cell data from the Gene Expression Omnibus (GSE202642) were used to assess the distribution of Climbing senecio’s bioactive targets within major HCC clusters. An intersection analysis of these clusters with pharmacological targets and HCC-related genes identified Climbing senecio’s primary targets for this disease. Cell communication, receiver operating characteristic (ROC)analysis, survival analysis, immune filtration analysis, and molecular docking studies were conducted for detailed characterization. Results: Eleven components of Climbing senecio were identified, along with 520 relevant targets, 300 differentially expressed genes, and 3765 co-expression module genes associated with HCC. AKR1B1, CA2, FOS, CXCL2, SRC, ABCC1, and PLIN1 were identified within the intersection of HCC-related genes and Climbing senecio targets. TGFβ, IL-1, VEGF, and CXCL were identified as significant factors in the onset and progression of HCC. These findings underscore the anti-HCC potential and mode of action of Climbing senecio, providing insights into multi-targeted treatment approaches for HCC. Conclusions: This study revealed that Climbing senecio may target multiple pathways and genes in the process of regulating HCC and exert potential drug effects through a multi-target mechanism, which provides a new idea for the treatment of HCC. However, the research is predicated on network database analysis and bioinformatics, offering insights into HCC therapeutic potential while emphasizing the need for further validation. Full article

Dendrobium devonianum is an important medicinal plant, rich in flavonoid, with various pharmacological activities such as stomachic and antioxidant properties. In this study, we integrated metabolome and transcriptome analyses to reveal metabolite and gene expression profiles of D. devonianum, both green (GDd) and purple-red (RDd) of semi-annual and annual stems. A total of 244 flavonoid metabolites, mainly flavones and flavonols, were identified and annotated. Cyanidin and delphinidin were the major anthocyanidins, with cyanidin-3-O-(6″-O-p-Coumaroyl) glucoside and delphinidin-3-O-(6″-O-p-coumaroyl) glucoside being the highest relative content in the RDd. Differential metabolites were significantly enriched, mainly in flavonoid biosynthesis, anthocyanin biosynthesis, and flavone and flavonol biosynthesis pathways. Transcriptomic analysis revealed that high expression levels of structural genes for flavonoid and anthocyanin biosynthesis were the main reasons for color changes in D. devonianum stems. Based on correlation analysis and weighted gene co-expression network analysis (WGCNA) analysis, CHS2 (chalcone synthase) and UGT77B2 (anthocyanidin 3-O-glucosyltransferase) were identified as important candidate genes involved in stem pigmentation. In addition, key transcription factors (TFs), including three bHLH (bHLH3, bHLH4, bHLH5) and two MYB (MYB1, MYB2), which may be involved in the regulation of flavonoid biosynthesis, were identified. This study provides new perspectives on D. devonianum efficacy components and the Dendrobium flavonoids and stem color regulation. Full article

Background/Objectives: Hemerocallis citrina Baroni (HCB) is a traditional herb for the treatment of depression in China. However, the active constituents and the underlying mechanisms of its antidepressant effects remain unclear. The aim of this study was to identify the bioactive constituents of HCB and elucidate its underlying mechanism for the treatment of depression. Methods: The constituents of HCB were systematically analyzed using UHPLC-Q-Orbitrap HRMS. Its antidepressant effect was evaluated by chronic unpredictable mild stress (CUMS)-induced depression. The mechanism of HCB in treating depression was investigated through network pharmacology and molecular docking. Subsequently, its potential mechanism for the treatment of depression was carried out by RNA sequencing. Finally, the mechanism was further verified by Western blot. Results: A total of 62 chemical constituents were identified from HCB using UHPLC-Q-Orbitrap HRMS, including 17 flavonoids, 11 anthraquinones, 11 alkaloids, 10 caffeoylquinic acid derivatives, five phenolic acids, five triterpenoids, and three phenylethanosides, 13 of which were identified as potential active constituents targeting 49 depression-associated proteins. Furthermore, HCB was found to significantly reduce cognitive impairment, anxiety-like behavior, and anhedonia-like behavior. The expression levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and brain-derived neurotrophic factor (BDNF) were elevated in the hippocampal CA3 region. Results from network pharmacology and transcriptomics indicated that the PI3K/Akt/CREB signaling pathway is essential for the therapeutic effects of HCB on depression. Research in the field of molecular biology has conclusively demonstrated that HCB is associated with an increase in the expression levels of several important proteins. Specifically, there was a notable upregulation of phosphorylated PI3K (p-PI3K) relative to its unphosphorylated form PI3K, as well as an elevation in the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, the study observed increased levels of phosphorylated CREB (p-CREB) compared to its unphosphorylated CREB. Conclusions: This study provides compelling evidence that HCB possesses the ability to mitigate the symptoms of depression through its influence on the PI3K/Akt/CREB signaling pathway. HCB could be developed as a promising therapeutic intervention for individuals struggling with depression, offering new avenues for treatment strategies that target this particular signaling mechanism. Full article

Background and Objectives: The Chansu injection (CSI), a sterile aqueous solution derived from Chansu, is applied in clinical settings to support antitumor and anti-radiation treatments. CSI’s principal active components, bufadienolides (≥90%), demonstrate potential effects on pancreatic cancer (PDAC), but their underlying mechanisms remain unclear. This study aimed to elucidate the antitumor effects and pathways associated with CSI in PDAC. Methods: Network pharmacology and bioinformatics analyses explored CSI’s mechanisms against PDAC. MTT, colony-formation, and migration assays evaluated CSI’s impact on proliferation and migration in PANC-1 and MIA PACA-2 cells, both as a single agent and in combination with erlotinib (EGFR inhibitor). Cell cycle analysis employed flow cytometry. Animal experiments were performed on tumor-bearing mice, with targets and pathways assessed via molecular docking and western blotting. Results: CSI treatment suppressed PDAC cell proliferation and migration by inducing G2/M phase arrest. Network pharmacology, bioinformatics, and molecular docking indicated that CSI’s anti-PDAC effects may involve EGFR pathway modulation, with CSI lowering p-EGFR/KRAS/p-ERK1/2 pathway expressions in PDAC cells. Additionally, sustained KRAS activation in mediating erlotinib resistance in PDAC and CSI potentiated erlotinib’s antitumor effects through enhanced KRAS and p-ERK1/2 inhibition. CSI also enhanced erlotinib’s efficacy in tumor-bearing mice without causing detectable toxicity in renal, cardiac, or hepatic tissues at therapeutic doses. Conclusions: CSI as an adjuvant used in antitumor and anti-radiation therapies enhanced erlotinib’s antitumor effects through modulation of the KRAS pathway. CSI and erlotinib’s synergistic interaction represents a promising approach for addressing erlotinib resistance in PDAC treatment. Full article

Obesity is a chronic disease that profoundly impacts human health, and the role of plant-based formulas (PBFs) in combating obesity has garnered significant interest. Studies have revealed that fermentation significantly enhances the taste, aroma, quality, and health benefits of PBF water extract, with pasteurization being the preferred sterilization technology. However, few studies have investigated the effects of pasteurization on the active components and potential functions of PBF water extract fermentation broth. To examine the impact of pasteurization on fermented water extract of Millettia speciosa Champ (FH08F) and its potential anti-obesity properties, the components of FH08F and thermal-pasteurized FH08F (FH08FS) were analyzed in this study. The analysis revealed a substantial rise in ester content following sterilization. This can be attributed to the acidic environment that promotes the esterification reaction during the heating phase. Network pharmacology was employed to thoroughly examine seven active components of upregulated compounds (URCs) with potential obesity targets, which constituted 92.97% of the total URC content, and four of them were nitrogen-containing aromatic heterocyclic compounds (NAHCs), which accounted for 90.33% of the total URC content. Upregulated NAHCs appear to actively contribute to efficacy against obesity. Molecular docking analyses have shown that theophylline, an NAHC, has the strongest binding affinity with the obesity-related target PTGS2 (Prostaglandin G/H synthase 2, 5FLG). These results imply that theophylline may directly activate PKA/PKG-mediated phosphorylated hormone-sensitive lipase (p-HSL), thereby promoting lipolysis through the cAMP signaling pathway and stimulating the catabolism of triglycerides (TGs) to combat obesity. In conclusion, pasteurization substantially alters the composition of FH08F, and NAHCs are likely to play a significant role in its potential anti-obesity function. These findings provide a scientific foundation for the potential therapeutic effect of FH08FS on obesity and associated metabolic diseases. Full article

Background: Caryopteris mongolica Bunge (CM) shows promising potential for managing rheumatoid arthritis (RA) and digestive disorders, attributed to its rich content of bioactive compounds such as polyphenols and flavonoids. Despite its common use in herbal tea, the specific mechanisms underlying CM’s anti-inflammatory and joint-protective effects remain unclear, limiting its development as a functional food. This study investigated the effects of aqueous CM extract on RA in collagen-induced arthritis (CIA) rats and explored the underlying mechanisms. Methods: Forty-eight female Sprague-Dawley rats were randomly assigned to six groups (n = 8): normal control, CIA model, methotrexate (MTX), and CM high-, middle-, and low-dose groups. Anti-inflammatory and joint-protective effects were evaluated using biochemical and histological analyses. To elucidate the mechanisms, we applied metabolomics, network pharmacology, and transcriptomics approaches. Results: The results demonstrated that CM extract effectively suppressed synovial inflammation in CIA rats, reducing joint degradation. CM’s anti-inflammatory effects were mediated through the TNF signaling pathway, modulating glycerophospholipid and amino acid metabolism, including reduced levels of tryptophan, LysoPC, and asparagine. Molecular docking identified scutellarin and apigenin as key bioactive compounds. Additionally, immunofluorescence analysis revealed CM’s therapeutic effects via TNF signaling inhibition and suppression of M1 macrophage polarization. Conclusions: These findings highlight the therapeutic potential of CM for RA and support its development as a functional food or pharmaceutical product. Full article

Citrus reticulata ‘Chachi’ (CRC), recognized for its considerable edible and medicinal significance, is a valuable source of metabolites beneficial to human health. This research investigates the metabolic distinctions and antioxidant properties across four different parts of CRC, using multivariate statistical analysis to interpret metabolomic data and network pharmacology to identify potential antioxidant targets and relevant signaling pathways. The results indicate considerable metabolic differences in different parts of the sample, with 1622 metabolites showing differential expression, including 816 secondary metabolites, primarily consisting of terpenoids (31.02%) and flavonoids (25.22%). The dried mature citrus peel (CP) section demonstrates the highest level of total phenolics (6.8 mg/g), followed by the pulp without seed (PU) (4.52 mg/g), pulp with seed (PWS) (4.26 mg/g), and the seed (SE) (2.16 mg/g). Interestingly, targeted high-performance liquid chromatography of flavonoids reveals the highest level of nobiletin and tangeretin in CP, whereas PU has the highest level of hesperidin, narirutin, and didymin. Furthermore, all four sections of CRC exhibit robust antioxidant properties in in vitro assessments (CP > PU > PWS > SE). Lastly, the network pharmacology uncovered potential antioxidant mechanisms in CRC. This research offers deeper insights into the development and utilization of byproducts in the CRC processing industry. Full article