Letter to the Editor: Advancing mechanistic and translational insights into ginger-extract-mediated protection against acrylamide-induced liver injury

Abstract

The study published in the World Journal of Hepatology by Nour El Deen et al investigated purified ginger extract’s protective effects against acrylamide-induced liver injury, focusing on phenotypic assessments (hepatic transaminases, hematoxylin and eosin staining, and oxidative stress). While results are visually informative, gaps remain. The material basis of ginger’s active components and mechanistic insights are underexplored. We propose future directions, including portal venous metabolite profiling, liver liquid chromatography-mass spectrometry, and single-cell transcriptomics to identify protective metabolites and molecular changes. Mechanistic validation via primary hepatocyte assays (apoptosis, inflammation, and oxidative stress) and high-throughput screening (genetic editing) could elucidate target pathways. Existing literature supports ginger’s hepatoprotective potential (anti-inflammatory, gut-liver crosstalk, and mitochondrial regulation), but deeper mechanistic exploration is warranted to enhance its translational value.

Key Words: Ginger extract; Acrylamide-induced liver injury; Metabolomics; Hepatoprotection; Therapeutic agents

Core Tip: This article highlights critical gaps in current research on ginger extract’s hepatoprotective effects against acrylamide-induced liver injury - namely, the undefined material basis of active components and superficial mechanistic insights. It proposes actionable solutions: Leveraging portal venous metabolomics, liver liquid chromatography-mass spectrometry profiling, and single-cell transcriptomics to map protective metabolites and molecular changes; validating mechanisms via primary hepatocyte assays (apoptosis, inflammation, oxidative stress); and applying high-throughput screening (genetic editing) to uncover target pathways. These directions are pivotal to transforming phenotypic observations into mechanistically robust, translatable insights for ginger-based liver protection.

TO THE EDITOR

We have read the study published in the World Journal of Hepatolog by Nour El Deen et al[1], which investigated the protective effects of purified ginger extract against acrylamide (ACR)-induced liver injury. The authors primarily conducted phenotypic studies, including assessments of hepatic transaminase expression, liver tissue hematoxylin and eosin staining to directly evaluate hepatocyte damage, and analysis of oxidative stress alterations. While the results are visually intuitive and straightforward, there remains a substantial scope for further investigation.

RESEARCH GAPS AND RECOMMENDATIONS FOR FUTURE METHODOLOGIES

Firstly, the material basis of the active components of ginger that exert protective effects against ACR-induced liver injury remains unclear. Although the authors performed quantitative and qualitative analyses of the purified ginger extract, enhancing the reproducibility and scientific rigor of the experiments, future studies could focus on analyzing its metabolites in the portal vein. Specifically, investigating portal venous metabolites, liver tissue liquid chromatography-mass spectrometry profiling, and single-cell transcriptomic analysis of liver tissues would help identify: (1) Changes in portal venous metabolites induced by ACR; (2) Effective metabolites of purified ginger extract entering the portal vein; and (3) Alterations in protective metabolites of ginger extract correlated with reduced liver damage. This approach would facilitate the screening of substances directly contributing to liver injury and identification of the protective effects of ginger while mapping the molecular atlas of liver changes to lay a foundation for mechanistic studies.

Secondly, mechanistic investigations should be deepened based on the effective portal venous metabolites of ginger. Using primary hepatocytes treated with key harmful metabolites from the ACR-induced portal vein, researchers could assess hepatocyte apoptosis, changes in key inflammatory factor pathways, and oxidative stress functions. Subsequent research in the protective metabolites of ginger extract from the portal vein would validate the efficacy of these functional changes and confirm the hepatoprotective effects of the active components of the ginger.

Additionally, based on the liver molecular atlas, high-throughput screening (e.g., genetic screening, gene knockout, and gene complementation) could identify target sites and novel mechanistic pathways of ginger’s effective metabolites in hepatocytes, further elucidating the molecular mechanisms underlying the hepatoprotective effects of ginger.

RESEARCH PROGRESS ON EFFECTIVE COMPONENTS OF GINGER EXTRACT AND THEIR BENEFICIAL EFFECTS ON LIVER METABOLISM

The academic community has initiated exploration of ginger extract’s benefits for mitigating liver inflammation and metabolic dysfunction. Jafari and Sahebkar[2] reported that ginger extract improves multiple cardiovascular and metabolic indicators (e.g., blood glucose, lipids, anthropometrics, blood pressure, inflammatory markers, and liver function), highlighting its multi-organ protective potential. Bhat et al[3] noted that most of ginger’s pharmacological activity stems from gingeroland its structural analogs: Regular administration of gingerol-rich extract to mice significantly downregulated pro-inflammatory cytokines [e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6] in the brain, exerting anti-inflammatory effects without severe side effects. Fatemi et al[4] found that oral 6-gingerol post-liver injury reduced blood levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, IL-6, and IL-1β, while ameliorating pathological liver damage. He et al[5] demonstrated that 6-gingerol activates the farnesoid X receptor to promote metabolism of toxic bile acids (e.g., deoxycholic acid), alleviating chronic cholestasis-induced liver/intestinal pathology and lowering total bile acids in serum, liver, and intestine. Collectively, these findings suggest that gingerol’s liver metabolic activity - its antagonism of oxidative stress from inflammation and its modulation of lipid/bile acid metabolism - are key directions for future research.

RESEARCH PROGRESS ON THE MOLECULAR MECHANISMS OF GINGEROL IN HEPATOCYTE PROTECTION

Scholars have further investigated the molecular mechanisms by which gingerol improves inflammation and hepatocyte metabolism. Widowati et al[6] have revealed that ginger extract protects hepatocytes by promoting IL-10 production while inhibiting NO, IL-1β, IL-6 levels, and the expression of Casp-3, Casp-9, and JNK genes. Xia et al[7] showed that 6-gingerol attenuates hepatic steatosis and metabolic dysfunction-associated steatohepatitis (MASLD) by activating the AMP-activated protein kinase-sterol regulatory element-binding protein signaling pathway, reducing triglyceride and cholesterol biosynthesis. Panyod et al[8] demonstrated that ginger extract prevents MASLD progression by altering gut microbiota and inhibiting the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells pathway - emphasizing its role in gut-liver axis-mediated anti-inflammation. These studies further elucidate, at the molecular level, how gingerol ameliorates MASLD and hepatocyte inflammation, providing a foundation for deeper research.

At the subcellular level, Yang et al[9] confirmed that ginger-derived extracellular vesicles restore mitochondrial dynamic balance (enhancing fusion, reducing fission), promote mitochondrial biogenesis, and improve mitochondrial dysfunction - directly protecting hepatocytes and suggesting potential as therapeutics for liver fibrosis. Han et al[10] summarized gingerol’s mitochondrial effects: 6-gingerol activates the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1α pathway to enhance mitochondrial biogenesis and energy expenditure. It also increases activity of antioxidant enzymes (glutathione peroxidase, superoxide dismutase), restores levels of citrate synthase, succinate dehydrogenase, NADPH oxidase, adenosine triphosphate, and the mitochondrial enzyme sirtuin 3, thereby improving hepatic mitochondrial antioxidant status, promoting the tricarboxylic acid cycle, and inhibiting steatosis. These findings indicate that gingerol’s protective effects on liver mitochondrial function may be the key to unraveling the broader biological effects of ginger extract.

CONCLUSION

In summary, gingerol - a core component of ginger extract - exhibits strong translational potential for liver protection. Its mechanistic basis, particularly regarding metabolite action, mitochondrial function, and gut-liver crosstalk, warrants further in-depth exploration.