1 Department of Pharmaceutical Chemistry, Malik Deenar College of Pharmacy, Kasaragod 671321
2 Biocon Biologics Limited, Bangalore
Non-alcoholic fatty liver disease (NAFLD) is a silent epidemic, affecting millions worldwide due to rising rates of obesity, insulin resistance, and sedentary lifestyles. It ranges from simple fat accumulation in the liver to more severe forms like non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. Despite its prevalence, no approved pharmacological treatments exist, and current strategies rely heavily on lifestyle modification. This review outlines the key mechanisms driving NAFLD progression—including lipid overload, oxidative stress, and cellular dysfunction—and explores the therapeutic promise of plant-derived compounds. Natural agents such as curcumin, silymarin, berberine, and chlorogenic acid show potential in reducing liver fat and inflammation. Emerging phytochemicals, such as cryptochlorogenic acid and Genkwanin, offer new hope for safer and more accessible interventions. By bridging molecular research with evidence-based phytotherapy, this review advocates for a holistic, patient-centered approach to NAFLD—one that integrates science, tradition, and sustainable care.
Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome characterised by increased fat deposition in the liver of patients not consuming alcohol.1 NAFLD is diagnosed by histopathology. The presence of hepatic steatosis even in the absence of secondary hepatic fat accumulation due to alcohol consumption, use of steatogenic medications, and hereditary factors is considered under the term NAFLD. The disease is associated with metabolic risk factors, including obesity, insulin resistance, and dyslipidaemia.2 Most of the patients are asymptomatic and show the symptoms of metabolic disorders.3 NAFLD can be simple steatosis (the deposition of fat without inflammation) or can develop into non-alcoholic steatohepatitis (NASH), which is a condition having inflammation along with fat deposition and also cellular damage in the liver. NASH may progress to fibrosis, Cirrhosis, or even hepatic carcinoma.4–6 (Figure 1).
Figure 1: Progression of NAFLD to NASH and liver cirrhosis.
The highest NAFLD prevalence was in Latin America 44.37% (30.66%-59.00%), then Middle East and North Africa (MENA) (36.53%, 28.63%-45.22%), South Asia (33.83%, 22.91%-46.79%), South-East Asia (33.07%, 18.99%-51.03%), North America (31.20%, 25.86%-37.08%), East Asia (29.71%, 25.96%-33.76%), Asia Pacific 28.02% (24.69%-31.60%), Western Europe 25.10% (20.55%-30.28%).7
The therapeutic goals of NAFLT are to reduce insulin resistance and cardiac end-organ damage, thereby prolonging the patient's survival. High-calorie intake is a major contributor to NAFLD development. So the management is mainly based on Moderate weight loss and increased physical activity.8 Currently, there are no approved specific drugs for treating NAFLD. However, several drugs approved for metabolic syndrome-related conditions, such as type 2 diabetes and hyperlipidemia, are available for patients. 9 Several new substances are currently in phase II and III of clinical development 10. Manually, the patients are recommended to change their lifestyle. Therefore, in the management of the disease, a comprehensive understanding of NAFLD pathology is essential.
PATHOLOGY OF NAFLD
Non-alcoholic fatty liver disease (NAFLD) begins with lipid buildup in the liver, and excessive fat accumulation increases the risk of disease progression. Key risk factors for developing hepatic fat and fibrosis include Age over 50, Obesity, Insulin resistance, Type 2 diabetes mellitus (T2DM), Elevated ferritin levels, and PNPLA3 I148M genetic polymorphism. While these risk factors are well established, the exact pathological mechanisms remain unclear.11
Ectopic fat accumulation is the presence/ deposition of fat droplets in non-adipose tissues that do not normally contain fat deposits. Excessive accumulation of lipid droplets in the liver contributes to insulin resistance. As a central visceral organ, the liver is particularly vulnerable to ectopic fat deposition. When body weight is elevated, the likelihood of developing cirrhosis increases significantly.12
Lipid accumulation and insulin resistance
APOB48 and APOB100 are triglyceride-rich lipoproteins that act as transporters of fatty acids to peripheral organs like the heart, adipose tissue, and skeletal muscles13. They also play a role in the absorption of chylomicrons from the intestine14. The very low-density lipoproteins (VLDL) and chylomicrons (CM) reaching the capillary lumen of the peripheral organ will convert into free fatty acids by lipoprotein lipase (LPL). The free fatty acids are then esterified for storage or oxidised to produce the required energy15,16. The breakdown of VLDL and CMs will result in the formation of remnant lipoproteins. The high concentration of LDL, VLDL, and remnant lipoproteins is associated with various cardiovascular disease conditions, as well as metabolic-associated fatty liver disease (MAFLD)17,18.
Insulin is an anabolic hormone that plays an important role in the storage of triglycerides in adipose tissue, the storage of free fatty acids in lipid droplets, and the inhibition of lipolysis19. In addition, insulin shows both anti-inflammatory and pro-inflammatory properties and controls the inflammation of peripheral tissues. Insulin resistance (IR) is the suboptimal response of receptors towards insulin. This condition triggers beta cells of the islet of Langerhans and may cause hyperinsulinemia. High caloric intake can damage insulin receptors, lead to increased glycolysis, and result in the release of free fatty acids20,21. So, insulin resistance and inflammation are interlinked factors and collectively influence the development of NAFLD and other metabolic disorders22,23.
Based on the studies on ob/ob Mice, it is found that the overexpression of the transcription factor SREBP 1c (Sterol Regulatory Element Binding Protein) is associated with increased lipogenesis in the liver. ChREBP (Carbohydrate Response Element Binding Protein) also plays a crucial role in the metabolism of carbohydrates and lipids. The expression of these transporters is very high in obese and these factors directly contribute to the high rate of lipogenesis and the development of hepatic steatosis24–26.
Hepatic lipotoxicity and oxidative stress
Hepatic lipotoxicity occurs when the liver's ability to use, store, and export free fatty acids (FFAs) as triglycerides (TGs) is surpassed by a large influx of FFAs from peripheral sources, primarily from adipose tissue27. This condition can also be exacerbated by increased de novo lipogenesis in the liver. Both of these factors are characteristic of insulin resistance and non-alcoholic fatty liver disease (NAFLD). Here, the level of free fatty acids is correlated with lipotoxicity. Saturated fatty acids are more hepatotoxic than unsaturated fatty acids28,29.
A single-nucleotide polymorphism of the PNPLA3 gene is associated with a higher likelihood of NAFLD. So, the inhibition of this enzyme/ knock out of the gene coding for the enzyme is a better treatment target30,31. The expression of HMG CoA reductase is very high in the liver tissue of patients with NAFLD. The accumulation of free cholesterol results in the presence of cholesterol crystals in lipid droplets, which is associated with fibrosing NASH32–34. Increased concentration of oxidised LDL causes inflammation of hepatic cells mediated by Kupffer cells, leading to NASH35.
Cholesterol is a major factor in the development of steatohepatitis induced by TNF (Tumour Necrosis Factor) and FAS (Fatty Acid Synthase). Free cholesterol depletes the mitochondrial glutathione. The decreased level of glutathione leads to the production of augmented reactive oxygen species (ROS). Uncontrolled oxidative stress can lead to significant damage to lipids. Reactive oxygen species (ROS) initiate lipid peroxidation by targeting polyunsaturated fatty acids, resulting in the production of highly reactive aldehyde compounds, such as 4-hydroxy-2-nonenal and malondialdehyde (MDA). Unlike free radicals, these reactive aldehydes have longer half-lives and can diffuse into the extracellular space, causing additional tissue damage36–38.
Endoplasmic Reticulum damage
The endoplasmic Reticulum is a cell organelle that has a major role in cellular protein synthesis. When the protein accumulation exacerbates the ER loading capacity, it will lead to endoplasmic reticulum stress (ERS). Transient ERS regulates protein homeostasis mediated by unfolded protein response (UPR), endoplasmic reticulum overload response (EOR), and sterol regulatory element–binding protein (SREBP), and reduces protein accumulation. But severe or strong ERS causes cell death39,40. The UPR is mediated by three key factors: protein kinase RNA-like ER kinase (PERK), which induces cell apoptosis; inositol-requiring enzyme 1 (IRE1), which promotes the activation of tumour necrosis factor (TNF), leading to inflammation and cell death; and activating transcription factor 6 (ATF6). As a result, ERS leads to inflammation and cell apoptosis, which in turn cause liver cell injury, ultimately progressing to NAFLD and NASH. ERS also activates SREBP-1c, a protein that increases the synthesis of fat by the liver27,41,42.
The use of medicinal plants in the management of NAFLD
Despite their clinical utility, conventional treatments often suffer from poor patient compliance, particularly among individuals with long-standing unhealthy lifestyle habits. Moreover, drugs such as bicyclol, silybin, elastase, and clofibrate are associated with adverse effects, including hepatotoxicity and exacerbation of hepatic steatosis. Consequently, there is growing interest in complementary and alternative therapies43,44.
The plant-based medicines are gaining attention in the current scenario because of the lower incidence of side effects and better therapeutic benefits. Various medicinal plants and their bioactive compounds can modulate hepatic lipid metabolism and are used widely in the management of hyperlipidaemia, diabetes, and NAFLD45.
Table 1: Various plants and their bioactive compounds having established uses in the treatment of NAFLD46–48
|
Plant |
Chemical constituent |
Proposed mechanism |
|
Curcuma longa |
Curcumin |
Antioxidant, anti-inflammatory, improves insulin sensitivity |
|
Silybum marianum
|
Silybin, silymarin |
Hepatoprotective, reduces lipid peroxidation, stabilizes membranes |
|
Camellia sinensis |
Epigallocatechin gallate |
Enhances lipid metabolism, reduces hepatic fat accumulation |
|
Glycyrrhiza glabra
|
Glycyrrhizin |
Anti-inflammatory, modulates lipid metabolism |
|
Berberis aristata |
berberine |
Activates AMPK, improves insulin resistance, reduces hepatic steatosis |
|
Panax ginseng |
Ginsenoside |
Modulates lipid metabolism, anti-inflammatory effects |
|
Phyllanthus niruri |
Lignans, flavonoids |
Antioxidant, hepatoprotective, reduces liver enzymes |
|
Ganoderma lucidum |
Polysaccharides, triterpenoids |
Immunomodulatory, reduces oxidative stress and inflammation |
|
Salvia miltiorrhiza |
Tanshinones, salvianolic acid |
Enhances microcirculation, reduces fibrosis and inflammation
|
|
Andrographis paniculata |
Andrographolide |
Anti-inflammatory, reduces hepatic lipid accumulation |
|
Punica granatum
|
Ellagic acid, punicalagin |
Antioxidant, improves lipid profile, protects hepatocytes |
|
Allium sativum |
Allicin, S-allyl cysteine |
Lipid-lowering, antioxidant, improves liver enzyme levels |
|
Zingiber officinale
|
Gingerol, shogaol |
Anti-inflammatory, improves hepatic steatosis and insulin resistance |
|
Cichorium intybus
|
Inulin, sesquiterpene lactones |
Prebiotic effect, improves lipid metabolism and liver function |
This review focuses on some current trends in herbal medicines used in the treatment of NAFLD.
1. Coffee
Coffee is a decoction prepared from the seeds of the coffee plant Cichorium intybus. Coffee contains various constituents that are isolated and detected early. Out of these 100s of constituents, some phenolic compounds are believed to have hepatoprotective activity49,50.
Table 2: Important chemical constituents of coffee and its proposed mechanism of action in the management of NAFLD.
|
Chemical constituent |
Structure |
Proposed mechanism of action |
|
|
Caffeine51 (Alkaloid) |
|
Inhibit the activation of hepatic stellate cells. Improve hepatic blood flow. |
|
|
Chlorogenic acids 52 (Polyphenols) |
|
Antioxidant property Prevent lipid peroxidation Inhibit liver carcinogenesis |
|
|
Cafestol & Kahweol (Diterpenes) |
|
Shows anti-inflammatory properties Antioxidant property |
|
|
Trigonelline (Alkaloid) |
|
Antioxidant Shows insulin-sensitizing effect |
|
Chlorogenic acid and caffeine show promising effects on reducing steatosis, inflammation, and fibrosis. Various in-vivo studies showed that coffee consumption improved hepatic steatosis, oxidative stress, and insulin resistance in animal models by upregulating peroxisomal proliferator-activated receptor (PPAR-g)53. Coffee extract can reduce fat deposition in the liver by improving the oxidation of fat and energy metabolism54. Trigonelline can prevent NAFLD by reducing the chances of cell apoptosis by inhibiting the Bax protein55.
2. Silphium perfoliatum (Cup plant)
Cup plant is an American plant that belongs to the Asteraceae family. The active ingredients found in the cup plant are flavonoids, polyphenols, and polysaccharides56. Polysaccharides are gaining large attention due to their various therapeutic properties, like antioxidant, antitumour, hypoglycaemic, and lipid-lowering properties57. Cup plant is rich in chlorogenic acid and exhibits properties such as lowering blood lipids, promoting weight loss, and hepatoprotective effects. 58,59
The studies on NAFLD mice revealed that Silphium perfoliatum plant extract significantly reduced the deposition of lipid droplets on hepatic HepG2 cells. The extract can reduce the metabolism of unsaturated fatty acids and control the generation of saturated fatty acids. The main component with lipid-lowering activity was found to be cryptochlorogenic acid. In-vitro and in-vivo studies suggested that cryptochlorogenic acid shows better activity than simvastatin.60
3. Tinospora crispa (petawali)
Tinospora crispa is a medicinal plant commonly found in the rainforests of Asia and Africa, belonging to the family Menispermaceae. This plant possesses various medicinal properties and is incorporated into various traditional medicines.61
The plant shows excellent hepatoprotective activity in biological and computational studies. The well-known constituents of this plant are a flavonoid, Genkwanin, alkaloids like berberine, palmatine, Jatrorrhizine, and a phenolic acid, Sinapic acid. These constituents have antioxidant and anti-inflammatory properties.62,63 Novel studies have identified a newer alkaloid, 6-methoxy-cannabisin I, which also exhibits anti-inflammatory properties.64
An in-silico study on Tinospora crispa using molecular dynamics emphasizes that the major phytoconstituents, such as 3′-O-methyl luteolin, Diosmetin, Genkwanin, and Luteolin, show potential efficacy against NAFLD.65
Table 3: Important chemical constituents of the plant Tinospora crispa with activity against NAFLD and their proposed target of action.
|
Chemical constituent |
Structure |
Target |
|
3’-O-methoxy luteolin |
|
Endothelial growth factor receptor (EGFR) PPARa,g,d Telomerase reverse transcriptase (TERT) |
|
Diosmetin |
|
CYP1A2, CYP3A4 and Fatty acid synthase |
|
Luteolin |
|
Matrix metalloproteinase 1 (MMP1) |
|
Genkwanin |
|
AKT1, STAT3 pathways |
CONCLUSION
NAFLD, or non-alcoholic fatty liver disease, is a common health issue that affects millions of people, often without obvious symptoms. This condition shows how modern lifestyles, stress, and food choices can affect liver health. While the science behind it is complex, the main idea is simple: our bodies need balance.
With knowledge of medicinal plants and new therapies, there are many ways to heal—beyond just using medications. Compounds like curcumin, silymarin, and berberine connect traditional remedies to modern science, offering hope when standard treatments are not enough. Newly discovered plant medicines like cryptochlorogenic acid from Silphium perfoliatum and Genkwanin from Tinospora crispa show the changing options for treating NAFLD.
Addressing NAFLD means more than just focusing on liver health. It requires changing one’s lifestyle, including diet, exercise, and self-care. We should take a proactive approach to our health, paying attention to our bodies before serious problems arise. This approach encourages a caring view of health, combining scientific evidence with personal experiences.
In short, whether one is a researcher, a clinician, or an individual seeking to understand their health journey, it is essential to acknowledge that incremental changes can yield significant benefits. The liver, resilient as it is, often requires a degree of support to restore its natural balance.
REFERENCES
P. Chithra, A. Sasindran, Lipid Dysregulation, Oxidative Stress, and ER Damage in NAFLD: Molecular Insights and Herbal Remedies, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 9, 1315-1325. https://doi.org/10.5281/zenodo.17106862
10.5281/zenodo.17106862
