The Potential Therapeutic Applications of Natural Products in the Oxidative Stress-Related MVA Pathway: Focus on HMGCR
Abstract
1. Introduction
2. Methods
3. Therapeutic Applications
3.1. Dyslipidemia/Hyperlipidemia (Also Summarized in Table 1)
3.1.1. Modulation of HMGCR Expression by Flavonoids and Phenolic Compounds
3.1.2. Impact of Traditional Chinese Medicine (TCM) and Herbal Formulations on HMGCR
3.1.3. Role of Specific Natural Products in HMGCR Regulation
3.1.4. Influence of Food Processing and Fermentation on HMGCR-Related Effects
3.1.5. Modulation of HMGCR Through the AMPK Pathway
3.1.6. Synergistic Effects and Combinations
Natural Product | Primary Bioactive Components | Dosage, Solvent for Extraction | Model System | HMGCR Effect | Proposed Mechanism | Reference |
---|---|---|---|---|---|---|
Coreopsis tinctoria Nutt. Extract | Luteolin, Marein, Naringenin, Chlorogenic Acid | Luteolin: 30 µM, marein: 10 µM, chlorogenic acid: 300 µM, naringenin: 200 µM | HepG2 cells (OA-induced) | Expression Downregulation | SREBP inhibition. | [18] |
Cocoa Shell Ingredients (CSF/CSE) | Phenolic Compounds, Dietary Fiber | phenolic compounds (CSE: 271.4 mg 100 g−1, CSF: 43.8 mg 100 g−1), flour and aqueous extract | In vitro, hepG2 cells | Activity Inhibition | HMGCR inhibition may be linked to the phenolic compounds and dietary fiber. These compounds could interact with the HMGCR active site, reducing its activity. | [29] |
Sanhua Jiangzhi Granules (SJG) | Complex Mixture of TCM Constituents | 10 μg/mL, methanol and water in a 4:1 ratio | Rat model (HF Diet) | Expression Downregulation | PPAR signaling pathway activation. | [20] |
Quercetin (from Buckwheat) | Quercetin | 25, 50, 75, 100, 150, and 200 µg/mL, hexane, ethylacetate, and methanol | HepG2 cells | Expression Downregulation | Not fully elucidated; synergistic with simvastatin. | [23] |
Forest Onion Extract (FOE) | Multiple—includes peptides | 35, 70, 105, 140, and 175 µg/mL, 96% ethanol | 3T3-L1 preadipocytes | Expression Downregulation | Inhibition of MAPK8, PPARG, HMGCR, CPT-1, and GLP-1 protein expressions. | [19] |
Lactiplantibacillus plantarum SDJ09 | Cell Extracts, Metabolites, Heat-Inactivated Cells | 30 μg/mL, sterile water | HepG2 cells | Expression Downregulation | Reduction in lipid synthesis, upregulation of cholesterol excretion. | [30] |
Alpiniae oxyphyllae Fructus (AOF) | Stigmasterol | 0, 1, 2, 4, 8, 16 µM | Cell experiments | N/A (not directly investigated the effect of AOF or its components on HMGCR expression or activity levels) | Upregulated the expression levels of ESR1 and PPARG to exert an anti-HUA effect. | [31] |
Taxus chinensis var. mairei (AETC) | Active Compound and Osimertinib combination | 0.03 to 2 mg/mL, double-distilled water | Osimertinib-resistant cells and xenograft tumors in nude mice | Expression Downregulation | ERK/SREBP-2/HMGCR-mediated cholesterol biosynthesis and ROS levels. | [28] |
Theabrownin from Qingzhuan tea (QTB) | Theabrownin extracted from Qingzhuan tea | 180 or 360 mg/kg/d, absolute ethanol, then distilled water | HFD-induced mice | Expression Downregulation | Upregulate the expression of ATGL, PPARα, FFAR2 and FFAR3, and inhibit the expression of LXRα, SREBP-1c, FAS and HMGCR genes. | [32] |
Sinapic Acid | A Natural Source of Simple Phenolic Acids | 0.03% | HFD-induced obesity hamster | Expression Downregulation | Egulationg the activities of PPAR-γ, CPT-1, and CYP7A1. | [24] |
DI-HET, hydroethanolic extract from Dillenia indica leaf | Naringenin, Catechin, Epicatechin, Shikimic Acid, Syringic Acid, Vanillic Acid, and Kaempferol | 5, 10, 20, 50, 100, 200, and 400 μg/mL, hydroethanolic extract | In vitro, HepG2 cells | Expression Downregulation | Activation of the SIRT-1/p-LKB-1/AMPK signaling pathway. | [33] |
Protium heptaphyllum Gum Resin Extract (PHE) | Acidic Tetra- and Pentacyclic Triterpenoids | 10–200 µg mL−1, hydroalcoholic extraction process | Hepatocytes | Expression Downregulation, Activity Inhibition | Reduce cholesterol production and regulate the expression of proteins involved in its metabolism. | [34] |
Virgin Camellia Seed Oil | Active Compounds in Vegetable Oil | 1.5 g/kg, squeezed using mall-pressed technologies | Sprague Dawley (SD) rats | Expression Downregulation | Modulating the AMPK-SREBP-signaling pathway. | [35] |
3.2. Cardiovascular Diseases (Also Summarized in Table 2)
3.2.1. Targeting HMGCR in Atherosclerosis
3.2.2. Modulation of HMGCR and Lipid Profiles by Natural Products
3.2.3. Novel HMGCR Degraders for Enhanced Statin Therapy
3.2.4. Black Elderberry Extract May Improve HDL Function
3.2.5. Influence of the Intestinal Flora on Atherosclerosis
Natural Product | Primary Bioactive Components | Dosage, Solvent for Extraction | Model System | HMGCR Effect | Proposed Mechanism | Reference |
---|---|---|---|---|---|---|
Tetrahydroxy stilbene glucoside (TSG) | N/A | 100 mg/kg/day | ApoE−/− mice | Expression Downregulation | Restores the expression of fatty acid metabolism-related genes. | [36] |
Schipenindolene A (Spid A) | Indole diterpenoid | 0.01–20 μM, trace fermented extract | In vitro cell culture | Protein Degradation | ERAD pathway activation. | [39] |
Arctium lappa leaves | Various (unspecified) | 12.5, 25, 50, 100, 200, and 400 μg/mL, 70% ethanol | Network pharmacology, in vitro and in vivo models | Did not directly measure HMGCR level | AMPK-mediated PPARG/LXRα pathway. | [37] |
Flaxseed oil | A-linolenic acid ester of PS (ALA-PS) | flaxseed oil: 5% (w/w), ALA-PS: 3.3% (w/w) | ApoE-KO mice | Expression Downregulation | Modulatory effects on the expression levels of genes involved in lipid metabolism, including PPARα, HMGCR, and SREBPs. | [38] |
Theabrownin from Qingzhuan tea (QTB) | Theabrownin extracted from Qingzhuan tea | 180 or 360 mg/kg/d, absolute ethanol, then distilled water | HFD-induced mice | Expression Downregulation | Possible to act as a prebiotic to prevent MASLD. Reduces the expression of the HMGCR. | [32] |
3.3. Cancer (Also Summarized in Table 3)
3.3.1. Targeting Cholesterol Synthesis in Cancer Therapy
Natural Product | Dosage, Solvent for Extraction | Cancer Type | HMGCR Effect | Proposed Mechanism | Reference |
---|---|---|---|---|---|
Cepharanthine (CE) | 0.1–20 μM | Small Cell Lung Cancer (SCLC) | Expression Downregulation | Inhibition of cholesterol synthesis, direct binding to HMGCR and other enzymes | [43] |
Taxus chinensis var. mairei (AETC) | 0.03 to 2 mg/mL, double-distilled water | EGFR-mutant NSCLC | Expression Downregulation | Regulation of ERK1/2, inhibition of cholesterol biosynthesis | [28] |
Gypenoside L | 10 mg/kg or 20 mg/kg, 95% ethanol fraction | Hepatocellular Carcinoma (HCC) | Expression Downregulation | Targeting the SREBP2-HMGCS1 axis, regulating the mevalonate pathway | [44] |
Carotenoids from Spondias mombin | 100 mg/kg and 200 mg/kg, n-hexane/acetone 1:1 (v/v) | Breast Cancer | Expression Downregulation | Hydrophobic interactions with key residues within the catalytic domain of HMGCR | [45] |
Chinese Red Yeast Rice (RYR) | 0–300 μg/mL, methylene chloride | Prostate Cancer, Colon Cancer | No Significant Influence on Expression | Mechanisms beyond HMGCR are likely involved (related to pigments) | [46,47] |
3.3.2. Cepharanthine as a Small Cell Lung Cancer Inhibitor via HMGCR Modulation
3.3.3. Taxus chinensis var. mairei Extract (AETC) to Overcome Osimertinib Resistance in Non-Small Cell Lung Cancer (NSCLC)
3.3.4. Gypenoside L as a Hepatocellular Carcinoma Inhibitor via HMGCR Regulation
3.3.5. Carotenoids from Spondias mombin Demonstrate HMGCR Inhibition
3.3.6. Chinese Red Yeast Rice (RYR)
4. Mechanisms of HMGCR Modulation by Natural Products
4.1. HMGCR as a Target
4.2. HMGCR Activity Inhibition
4.3. HMGCR Expression Regulation (Also Summarized in Table 4)
4.3.1. Downregulation of HMGCR Expression
4.3.2. SREBP-2 Modulation
4.3.3. AMPK Activation
4.3.4. Other Mechanisms
Natural Product/Extract | Effect on HMGCR Expression | Mechanism | Reference |
---|---|---|---|
Coreopsis tinctoria Nutt. extracts (luteolin, marein, NGN, CQA) | Downregulation | Reduce OA-induced oxidative stress and lipid accumulation | [18] |
Aqueous extract of Taxus chinensis var. Mairei | Downregulation | ERK/SREBP-2/HMGCR-mediated cholesterol biosynthesis | [28] |
Flavonoid-rich extract of Paulownia fortunei Flowers | Decrease | AMPK pathway | [60] |
GINST (hydrolyzed ginseng extract) | Decrease | AMPKα activation | [59] |
Sargassum fusiforme polysaccharide (SFP) co-administered with low-dose acarbose | Decrease in the expression of the HMGCR gene | Affecting the expression of HMGCR and SREBP-1c genes, restraining liver fat accumulation | [63] |
Flaxseed oil (FO), a dietary oil rich in α-linolenic acid | Decreased protein expression | Decreased the protein expression of SREBP2, HMGCR, and LDLR while increasing the expression of CYP7A1 | [57] |
Annatto-derived tocotrienol | Downregulated HMGCR gene expression | Downregulating HMGCR gene expression and inhibiting RhoA activation, leading to increased BMP-2 protein | [64] |
Celastrus orbiculatus Thunb. | Upregulated HMGCR mRNA | LDL-R, SR-B1, CYP7A1 | [61] |
Black raspberry extract | Downregulated Srebf2 and Hmgcr expressions | Upregulate and enhance Cyp7a1 and Abcg5 expressions | [62] |
4.4. Signaling Pathways Involvement (Also Summarized in Table 5)
4.4.1. SREBP Pathway
4.4.2. PPAR Pathway
4.4.3. AMPK Pathway
4.4.4. ERK1/2 Pathway
4.4.5. PI3K-Akt Pathway
4.4.6. mTOR Pathway
Natural Product or Extract | Signaling Pathway(s) Involved | Effect on HMGCR | Reference |
---|---|---|---|
Sanhua Jiangzhi Granules | PPAR | Downregulation | [20] |
Taxus chinensis var. Mairei Extract | ERK/SREBP-2 | Downregulation | [28] |
Virgin Camellia Seed Oil | AMPK-SREBP | Downregulation | [35] |
Unripe Rubus coreanus Extract and Ellagic acid | AMPK, SREBP-2 | Reduce HMGCR Activity | [58] |
Red Raspberry Extract | PPAR | Downregulation | [65] |
Flavonoid-rich Extract of Paulownia fortunei Flowers | AMPK | Decrease | [60] |
Strawberry Methanolic Extract | AMPK | Inhibition | [66] |
Gandi capsule | AMPK, PI3K-Akt | HMGCR identified as a potential target | [67] |
Zexie Tang | FKBP38/mTOR/SREBPs | Downregulation | [56] |
4.5. Comparison or Combination with Statins or Other Therapies (Also Summarized in Table 6)
Natural Inhibitor/Extract | Potency Compared to Statins | Key Mechanisms | Reference |
---|---|---|---|
Quercetin | Synergistic with Simvastatin | Reduces HMGCR expression, increases CYP7A1 expression. | [23] |
Chlorogenic Acid-Enriched Extract from Eucommia ulmoides leaves | Lower IC50 than Simvastatin | Increases ABCA1, CYP7A1, and AMPKα2 mRNA expression, decreases SREBP2. | [71] |
Curcuma Oil | Comparable to Ezetimibe (at high dose) | Modulates PPARα, LXRα, and associated genes in lipid metabolism and transport. | [72] |
Forest Onion Extract | N/A | inhibits targeted protein expressions of MAPK8, PPARG, HMGCR, CPT-1, and GLP-1 in vitro in 3T3-L1 mouse cells. | [19] |
Red Yeast Rice | N/A (In contrast to LV, neither RYR nor PF-RYR significantly altered the expression of HMGCR or SREBP-2) | Exhibit anticancer effects on colon cancer cells. May affect intracellular signaling pathways differently from purified crystallized LV. | [47] |
Sargassum fusiforme polysaccharide (SFP) | N/A | Restores beneficial gut flora and activates IRS/PI3K/AKT signaling pathway (in combination with low-dose acarbose). Restrained liver fat accumulation via affecting the expression of HMGCR and SREBP-1c genes. | [63] |
5. Challenges and Future Directions
5.1. Research Gaps in Natural HMGCR Modulators
5.2. Challenges in Translating In Vitro Data to Clinical Application
5.3. Clinical Trial Suggestion
5.3.1. Hyperlipidemia
5.3.2. Cardiovascular Disease
5.3.3. Cancer
5.4. Need for Mechanistic Elucidation
5.5. Limitations in Natural Product Development
5.6. Bioavailability, Metabolism, and Safety Considerations
5.7. Potential Interactions with Conventional Medications
5.8. Batch-to-Batch Variability Challenges
5.9. Potential Risks of Natural Products
5.10. Priorities for Future Research
6. Conclusions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ABCA1 | ATP-binding cassette transporter A1 |
ABCG5 | ATP-binding cassette transporter G5 |
ACAT | Acyl CoA–cholesterol acyltransferase |
AETC | Aqueous extract of Taxus chinensis var. Mairei |
ALA-PS | α-linolenic acid ester of plant sterols |
AMPK | AMP-activated protein kinase |
AnTT | Annatto-derived tocotrienol |
AOF | Alpiniae oxyphyllae Fructus |
AS | Atherosclerosis |
ATGL | Adipose triglyceride lipase |
BEE | Black elderberry extract |
BMP-2 | Bone morphogenetic protein-2 |
CCL2 | Chemokine (C-C motif) ligand 2 |
CE | Cepharanthine |
CI | Combination index |
CPT-1 | Carnitine palmitoyltransferase 1 |
CQA | Chlorogenic acid |
CRP | C-Reactive Protein |
CSF/CSE | Two cocoa shell ingredients, a flour (CSF) and an aqueous extract (CSE) |
CVD | Cardiovascular disease |
CYP7A1 | Cholesterol 7α-hydroxylase |
DI-HET | Hydroethanolic extract from Dillenia indica leaf |
ERAD | Endoplasmic reticulum-associated degradation |
ERK | Extracellular signal regulated kinase |
ESR1 | Estrogen receptor 1 |
FAS | Fatty acid synthase |
FABP | Fatty-acid-binding proteins |
FAT | Fatty-acid translocase |
FATP | Fatty acid transport proteins |
FDFT1 | Farnesyl-Diphosphate Farnesyltransferase 1 |
FFAR | Free fatty acid receptors |
FKBP38 | FK506-binding protein 8 |
FOE | Forest onion extract |
GINST | A hydrolyzed ginseng extract |
GLP-1 | Glucagon-like peptide 1 |
Gyp L | Gypenoside L |
HCC | Hepatocellular carcinoma |
HDL | High-density lipoprotein |
HepG2 | Hepatocellular carcinoma cell line |
HFD | High-fat diet |
HMG-CoA | 3-Hydroxy-3-methylglutaryl-CoA |
HMGCR | HMG-CoA reductase |
HMGCS1 | 3-Hydroxy-3-methylglutaryl-CoA synthase 1 |
HSD11B1 | 11β-Hydroxysteroid dehydrogenase 1 |
HSYA | Hydroxysafflor yellow A |
HUA | Hyperuricemia |
IDI1 | Isopentenyl-diphosphate delta-isomerase |
IRS | Insulin receptor substrate |
LDL | Low-density lipoprotein |
LDL-C | Low-density lipoprotein cholesterol |
LDLR | LDL receptor |
LV | Lovastatin |
LXRα | Liver X receptor α |
MAPK8 | Mitogen-activated protein kinase 8 |
MASLD | Metabolic dysfunction-associated steatosis liver disease |
mTOR | Mammalian target of rapamycin |
MVA | Mevalonate pathway |
NGN | Naringenin |
NOS2 | Nitric oxide synthase 2 |
OA | Oleic acid |
OS | Overall survival |
ORR | Objective response rate |
PCSK9 | Proprotein convertase subtilisin/kexin type 9 |
PFS | Progression-free survival |
PHE | Protium heptaphyllum Gum Resin Extract |
PI3K-Akt | PI3K (phosphatidylinositol 3-kinase) and Akt (protein kinase B) |
p-LKB-1 | Phospho-liver kinase B1 |
PPAR | Peroxisome proliferator-activated receptors |
PTGS2 | Prostaglandin G/H synthase 2 |
QTB | Theabrownin from Qingzhuan tea |
RAD | Radix Angelica dahuricae |
RCT | Randomized controlled trials |
ROS | Reactive oxygen species |
RYR | Red yeast rice |
SCLC | Small cell lung cancer |
SFP | Sargassum fusiforme polysaccharide |
SIRT-1 | Sirtuin 1 |
SJG | Sanhua Jiangzhi Granules |
SLXG | Shugan Lidan Xiaoshi Granules |
Spid A | Schipenindolene A |
SQLE | Squalene epoxidase |
SR-B1 | Scavenger receptor class B type 1 |
SREBP-2 | Sterol regulatory element-binding protein 2 |
TC | Total cholesterol |
TCM | Traditional Chinese Medicine |
TG | Triglyceride |
TSG | Tetrahydroxy stilbene glucoside |
UME | Ulmus macrocarpa Hance |
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Teng, Y.-N. The Potential Therapeutic Applications of Natural Products in the Oxidative Stress-Related MVA Pathway: Focus on HMGCR. Antioxidants 2025, 14, 1001. https://doi.org/10.3390/antiox14081001
Teng Y-N. The Potential Therapeutic Applications of Natural Products in the Oxidative Stress-Related MVA Pathway: Focus on HMGCR. Antioxidants. 2025; 14(8):1001. https://doi.org/10.3390/antiox14081001
Chicago/Turabian StyleTeng, Yu-Ning. 2025. "The Potential Therapeutic Applications of Natural Products in the Oxidative Stress-Related MVA Pathway: Focus on HMGCR" Antioxidants 14, no. 8: 1001. https://doi.org/10.3390/antiox14081001
APA StyleTeng, Y.-N. (2025). The Potential Therapeutic Applications of Natural Products in the Oxidative Stress-Related MVA Pathway: Focus on HMGCR. Antioxidants, 14(8), 1001. https://doi.org/10.3390/antiox14081001