Background: Natural bioactive components derived from plant secondary metabolites have been pronounced as valuable alternatives for anticipating and subsiding hepatotoxic effects and its chronic complications based on experimental verification. The focus of this review is to elucidate the commonly used modern medicine for the treatment of liver disease and how major phytoconstituents have been tested for hepatoprotective activity, mechanism of action of some promising agents from natural sources, and clinical trial data for treating in patients with different liver diseases by the aid of natural phytoconstituents.Main text: The review shows fifteen major isolated phytoconstituents, their biological sources, chemical structures, utilized plant parts, type of extracts used, hepatoprotective assay method, and their possible mechanism of action on the hepatoprotection. Nine promising hepatoprotective leads from natural sources with their chemistry and hepatoprotective mechanism are mentioned briefly. The review further includes the recent clinical trial studies of some hepatoprotective leads and their clinical outcome with different liver disease patients. Scientific studies revealed that antioxidant properties are the central mechanism for the phytoconstituents to subside different disease pathways by upsurging antioxidant defense system of cells, scavenging free radicals, down surging lipid peroxidation, improving anti-inflammatory potential, and further protecting the hepatic cell injury. In this review, we summarize recent development of natural product-based hepatoprotective leads and their curative potential for various sort of liver diseases. Furthermore, the usefulness of hit and lead molecules from natural sources for significant clinical benefit to discover new drug molecule and downsizing the problems of medication and chemical-induced hepatotoxic effects is extrapolated.Conclusion: Further research are encouraged to elucidate the pharmacological principle of these natural-based chemical agents which will stimulate future pharmaceutical development of therapeutically beneficial hepatoprotective regimens.

Liver cancer is one of the most prevalent malignant diseases in humans and the second leading cause of cancer-related mortality globally. Angiopteris helferiana was mentioned as a possible anticancer herb according to ethnomedicinal applications. However, the molecular docking and chemical profiling of the bioactive phytoconstituents accountable for the reported anticancer action still require research. The present study aims the phytochemical profiling and bioactivity evaluation of A. helferiana. The study design with in-vitro and in-silico technique of the LC-MS followed by a study of the ligand–protein interaction using the molecular docking method, and investigates the cytotoxic activity by MTT assay of A. helferiana bioactive compounds on HepG2 cell lines. LC-MS results detected seventeen phytoconstituents in A. helferiana extract belonging to variable chemical classes with most prevailing compounds such as Vicenin 1, Schafroside, Violanthin, Coumarin, Quercetin, Angiopterioside, and Corosolic acid. The finding concluded that Quercetin showed significant binding energy of -8.8 kcal/mol and then Schafroside also possesses the binding energy of -8.1 kcal/mol against the human PPAR-δ receptor (PDBID: 1I7G). The extract showed the moderate cytotoxic activity having IC₅₀ value of 236.93 μg/mL. Our finding suggests that these bioactive compounds could be developed as promising anticancer agent, but further in-vivo study require to validate the finding along with isolation of individual phytoconstituents.

Juglans regia L. is a well‐known therapeutic plant in Nepal, employed in traditional medicine for treating liver ailments. This study aimed to evaluate the in vivo and in silico liver‐protective effects of J. regia extract using a carbon tetrachloride (CCl₄)‐induced hepatic damage rat model. Healthy male rats were randomly divided into six groups: normal control (distilled water 10 mL/kg), toxic control (distilled water 10 mL/kg), standard test (silymarin 100 mg/kg), and three groups receiving oral J. regia extracts (125, 250, and 500 mg/kg/day) for seven days. On the eighth day, carbon tetrachloride (CCl₄) was administered intraperitoneally (i.p.) (1.5 mL/kg in 1:1 olive oil ratio for all groups, except the normal control). Rats were sacrificed on the ninth day, and blood was collected retro‐orbitally for liver blood injury tests and histopathological studies. Molecular docking was performed against cytochrome P450 2E1 (CYP450 2E1) enzyme for 16 selected phytoconstituents. J. regia, at doses of 125, 250, and 500 mg/kg, significantly reduced liver enzyme levels (alanine aminotransferase, alkaline phosphatase, direct bilirubin, and total bilirubin), while increasing serum albumin. Histological analysis revealed mitigation of carbon tetrachloride (CCl₄)‐induced liver injury, reducing fatty degeneration and necrosis. Molecular docking supported the findings, with Beta‐sitosterol and Betulinic acid exhibiting the best binding affinity of −9.2 and −9.1 kcal/mol, respectively. In conclusion, result suggests that J. regia showed dose‐dependent hepatoprotective activity in CCl₄‐induced hepatotoxicity and it could be utilized as a promising hepatoprotective agent. This study suggests the hepatoprotective potential of J. regia bark extracts, emphasizing the need for further clinical validation.

In 2019, diabetes mellitus affected 9.3% of the global population and accounted for one in nine adult deaths. Plant‐based antioxidants neutralize harmful free radicals, mitigate oxidative stress, and significantly prevent diabetes and its complications. This study evaluated the in vitro antioxidant, alpha‐amylase inhibitory, in vivo oral hypoglycemic, and in silico antidiabetic potential of Smallanthus sonchifolius (S. sonchifolius) leaf extract. Mice (n = 25) were divided into five groups after a 16‐h fast with access to water. The groups received distilled water (normal control), metformin (100 mg/kg, standard), or S. sonchifolius ethanolic extract at 100, 250, or 500 mg/kg to compare the antidiabetic potential of the extract with that of the control. Fasting blood glucose levels were measured in tail vein blood before the experiment and at 30, 60, and 120 min post‐administration to evaluate the hypoglycemic activity of the extract and standard drug. The ethanolic extract exhibited dose‐dependent alpha‐amylase inhibition (IC₅₀ value 0.136 mg/mL) and significant hypoglycemic effects, reducing blood glucose levels similar to those of the standard drugs voglibose and metformin. The maximum blood glucose reduction was 17.99% and 15.74% in the normal and glucose‐loaded mice, respectively, at 500 mg/kg within 120 min. In silico analysis shows, polymatin B and chlorogenic acid demonstrating the highest binding affinity of −8.2 and −7.2 kcal/mol, respectively, in PPAR‐γ (3G9E). Polymatin B and chlorogenic acid showed strong binding affinities of −7.3 and −7.5 kcal/mol, respectively, in alpha‐amylase (4W93). These findings indicate that S. sonchifolius possesses significant hypoglycemic and antioxidant properties, suggesting its potential as an antidiabetic agent, warranting further clinical research.

Jumli Marshi (J. Marshi), a native rice cultivar in Nepal, is gaining popularity owing to its health benefits for obesity, hypertension, and diabetes. However, scientific evidence verifying its therapeutic potential is lacking until November 2024. Therefore, we aimed to characterize the phytoconstituents and evaluate the antioxidant, antibacterial, and antidiabetic properties of J. Marshi, along with its ADME toxicity profile, using both in vitro and in silico approaches. Liquid chromatography-mass spectrometry analysis of a 70% methanol extract from J. Marshi identified ten plant-based compounds, including phenolic acids, flavonoids, and γ-oryzanol. The extract exhibited significant antioxidant properties, neutralizing DPPH free radicals with a fifty-percentage inhibitory concentration (IC₅₀) of 42.65 ± 3.9 µg/mL, compared to ascorbic acid’s IC₅₀ of 4.12 ± 0.7 µg/mL. It also showed antibacterial activity against Staphylococcus aureus, with a zone of inhibition (ZOI) ranging from 7 to 11 mm and a minimum inhibitory concentration (MIC) of 1.56 mg/mL, compared to standard antibiotics meropenem (ZOI: 24 ± 1.6 mm; MIC: 1.56 mg/mL). The enzymatic assay demonstrated that the J. Marshi extract inhibits fifty percent of enzyme activity at a concentration (EC₅₀) of > 1000 µg/mL for α-amylase and 250 ± 2.5 µg/mL for α-glucosidase, in contrast to the standard acarbose, exhibiting an EC₅₀ of 35.5 ± 1.5 µg/mL for α-amylase and 189.5 ± 1.9 µg/mL for α-glucosidase. In silico docking studies revealed strong interactions of rice phytoconstituents with target protein catalytic residues, particularly gamma-oryzanol for α-amylase (−10.0 kcal/mol) and chlorogenic acid for α-glucosidase (−7.7 kcal/mol), compared to acarbose (−6.9 to −7.1 kcal/mol). ADME toxicity analysis suggested that tricin and gamma-oryzanol had the best drug-likeness and safety profiles. To our knowledge, this is the first study to reveal the presence of bioactive phenolic acids and flavonoids. Furthermore, it offers scientific evidence supporting significant antioxidant and α-glucosidase-inhibitory properties, confirming the potential applications of J. Marshi rice as a functional food used for the management of diabetes.

Diabetes is among the top ten causes of mortality and morbidity. Diabetes has been increasing faster in low‐ and middle‐income nations than it has been rising in high‐income countries. This study explores the phytochemical profiling and in vitro α‐amylase inhibitory activity of the methanolic extract of Nepalese‐origin pomegranate peels. Phytochemical analysis using FT‐IR and LC–MS identified key bioactive compounds, including ellagic acid, punicalagin, punicalin, gallic acid, and ellagic acid‐O‐xylopyranoside, contributing to the observed enzymatic inhibition. Molecular docking studies revealed strong binding affinities of punicalagin (−11.6 kcal/mol) and ellagic acid‐O‐xylopyranoside (−10.6 kcal/mol) to α‐amylase, suggesting potential antidiabetic properties. MD simulations confirmed the stability of these interactions over a 100 ns timeframe, reinforcing their role in enzyme inhibition. The in vitro α‐amylase inhibition assay demonstrated comparable activity of pomegranate peel extract (IC ₅₀ = 137.74 μg/mL) to reference drug acarbose (IC ₅₀ = 222.19 μg/mL). These findings provide molecular insights into the bioactivity of pomegranate peel extracts, highlighting their potential in diabetes management.