Ginger as a nutraceutical shield: Counteracting acrylamide-induced liver injury

Abstract

Acrylamide, a contaminant formed during high-temperature cooking of common foods, is increasingly recognized as a silent and underestimated contributor to liver injury. In this editorial, we comment on the study by Nour El Deen et al, demonstrating that a chemically standardized ginger (Zingiber officinale) extract (≥ 20% 6-gingerol) mitigates acrylamide-induced hepatotoxicity in rats through antioxidant, anti-inflammatory, and cytoprotective mechanisms. By combining biochemical, histopathological, and molecular evidence, the authors establish a coherent experimental basis for future translational research. Their results are consistent with a growing body of data supporting the hepatoprotective properties of ginger and emphasize the importance of using standardized nutraceutical preparations in preventive hepatology. From a precision-nutrition perspective, ginger phytocompounds appear to influence key oxidative, inflammatory, and metabolic pathways, possibly involving the gut-liver axis. Confirmatory studies in chronic exposure models and human cohorts, together with compositional and protein-level validation, will be essential to strengthen both the mechanistic and translational significance of these findings.

Key Words: Ginger; Acrylamide exposure; Hepatotoxicity; Oxidative stress; Precision nutraceuticals

Core Tip: Acrylamide, a common food contaminant, contributes to liver injury through oxidative and inflammatory mechanisms. Nour El Deen et al demonstrate that a standardized ginger extract (≥ 20% 6-gingerol) protects against acrylamide-induced hepatotoxicity in rats. The editorial highlights the broader implications of such findings: Standardized nutraceuticals can serve as accessible tools for preventive hepatology. Within a precision-nutrition context, rigorous compositional and molecular validation will be essential to translate these preclinical observations into human relevance.

INTRODUCTION

Since its discovery in staple foods such as fried potatoes and bread in 2002[1], acrylamide has been classified as a probable human carcinogen and a vinyl monomer of global toxicological concern[2]. Recent reviews have highlighted that acrylamide is ubiquitous in cereal-based foods and coffee, with coffee alone representing a significant source of global dietary exposure. In addition, human exposure to acrylamide can also occur through different routes, including contaminated materials, skin contact, and inhalation. The health risks of prolonged exposure have been documented[3]. Short- and medium-term exposures can also be objectively monitored through validated biomarkers, including hemoglobin adducts and urinary mercapturic acids, which strengthen exposure-effect inference[4].

Hepatic metabolism through cytochrome P450 2E1, in both humans and experimental animals, generates glycidamide, a reactive metabolite capable of forming DNA and protein adducts[5]. In the liver, this process initiates a cascade of oxidative stress, lipid peroxidation, and chronic inflammatory signaling, which are likely to play a key role in the carcinogenicity and neurotoxicity of acrylamide[6]. Additional evidence implicates mitochondrial dysfunction, dysregulated autophagy, and gut microbiota disturbance in acrylamide-induced hepatotoxicity[7].

Moreover, dietary exposure impacts multiple organs beyond the liver, including kidneys[8], the gastrointestinal tract[9], the reproductive system[10], and the cardiovascular system[11], underscoring its systemic toxicity. Recent human evidence has also suggested links with extrahepatic outcomes, such as an association between acrylamide/glycidamide exposure and psoriasis[12]. As diets rich in ultra-processed foods remain widespread, acrylamide represents an unavoidable daily exposure and an underestimated contributor to the global burden of chronic disease[13]. The urgency of this issue is reflected in new technological approaches, such as the development of electrochemical biosensors for rapid and sensitive detection of acrylamide in food products[14]. However, such technologies primarily serve surveillance purposes and cannot effectively reduce population exposure, highlighting the need for complementary preventive strategies. Nutraceutical interventions, in particular, offer a biologically grounded means of mitigation through modulation of oxidative and inflammatory pathways.

At the regulatory level, the European Food Safety Authority published in 2015 a scientific opinion on acrylamide in food, concluding that dietary exposure to acrylamide potentially increases the risk of developing cancer in consumers of all age groups[15]. Subsequently, the European Commission adopted Commission Regulation (EU) 2017/2158, which sets mitigation measures and benchmark levels for the reduction of acrylamide in certain foods[16]. In the United States, the Food and Drug Administration issued in 2016 its “Guidance for Industry: Acrylamide in Foods”, which provides non-binding recommendations for manufacturers on practices to reduce acrylamide formation during food processing[17].

At the same time, research is increasingly embracing systems-biology approaches: Transcriptomics and metabolomics are being applied to elucidate the multilevel toxicity of acrylamide. Such approaches underscore that acrylamide toxicity results from interconnected oxidative, inflammatory, and metabolic disturbances, the kind of complexity for which pleiotropic nutraceuticals, such as ginger (Zingiber officinale), are particularly well suited[6,18].

Finally, the concept of “precision nutraceuticals” is gaining traction: Individual variability in enzymes such as cytochrome P450 2E1 may influence toxic susceptibility and response to dietary interventions[19,20]. This perspective aligns with the broader field of personalized nutrition, which highlights genetic and metabolic variability as critical determinants of response to dietary agents[21]. Future studies should also consider advanced formulations (e.g., nanoemulsions or targeted delivery systems) to improve bioavailability and consistency[22,23]. Within this broader precision framework, the gut-liver axis has emerged as a key target, linking diet, microbiota, and hepatic health. Evidence indicates that acrylamide disrupts intestinal homeostasis, whereas ginger phytocompounds can restore microbial balance and reduce endotoxin-driven inflammation[24]. Consistent with this view, studies in humans and animal models have shown that ginger and its main constituents, including 6-gingerol, can modulate gut microbiota composition, promoting beneficial microbial profiles and reducing pro-inflammatory communities[24,25]. Against this mechanistic and translational background, the study by Nour El Deen et al[26] is particularly noteworthy: It not only supports the hepatoprotective potential of standardized ginger extract against acrylamide-induced injury but also exemplifies the broader paradigm of how traditional remedies can be repositioned within molecular hepatology, bridging ancient wisdom and modern precision medicine.

MECHANISTIC PLAUSIBILITY, STRENGTHS AND LIMITATIONS

The study provides coherent biochemical and histological evidence of protection. However, protein-level validation of gene expression and a more detailed phytochemical characterization of the ginger extract would further enhance mechanistic understanding and reproducibility. In this commentary, we therefore expand the discussion by summarizing the main phytochemicals and their molecular targets to contextualize the findings within the broader framework of ginger’s hepatoprotective mechanisms. Occasional editorial inaccuracies, such as a sporadic mention of “acetaminophen” instead of acrylamide, have no material impact on data interpretation.

The biological plausibility of these observations is consistent with existing data on ginger phytochemistry. Gingerols and shogaols are known to activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway while inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated transcription of pro-inflammatory mediators, thereby reinforcing antioxidant defenses and limiting inflammatory signaling[23,27]. In hepatic models, 6-gingerol attenuates apoptosis during ischemia/reperfusion injury through BCL2-associated X protein/B-cell lymphoma 2 modulation, and zingerone exerts similar cytoprotective effects. Broader reviews also report a reduction in the BCL2-associated X protein/B-cell lymphoma 2 ratio and suppression of apoptotic cascades with ginger extracts[28,29]. These pleiotropic properties help explain ginger’s benefits across diverse models of hepatic injury, including foodborne toxicants such as acrylamide. Additional mechanisms include AMP-activated protein kinase (AMPK)-sterol regulatory element-binding protein regulation by 6-gingerol[30], and improved hepatic antioxidant defense and lipid metabolism in high-fat diet-fed mice[31], as well as nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3-microbiota modulation by ginger essential oil[24], both relevant to lipid metabolism and inflammation.

Recent omics-based studies further confirm that ginger phytocompounds orchestrate complex gene networks involved in oxidative stress, inflammation, and metabolism, providing a systems-level rationale for hepatoprotection[18,32]. On this basis, it is useful to summarize the major bioactive constituents of Zingiber officinale and their molecular targets (Table 1), as they offer a mechanistic framework that complements the observations by Nour El Deen et al[26].

Table 1 Major bioactive compounds of Zingiber officinale with hepatoprotective effects and their associated signaling mechanisms.

Phytochemical components	Biological effects	Signaling pathways	Ref.
6-gingerol	Inhibits invasion and metastasis; blocks angiogenesis; induces apoptosis; exhibits hepatoprotective effect	NF-кB decrease, STAT3 decrease, MAPK decrease, PI3K/AKT-P21 increase, AMPK increase, BAX increase	[33-35]
8-gingerol	Exhibits antiemetic activity; reduces ROS production; modulates autophagy; inhibits proliferation and migration; induces apoptosis	Nrf2-HO-1 increase, 5-hydroxytryptamine 3 antagonist; neurokinin-1 antagonist modulates EGFR/STAT/ERK signaling, PI3K/AKT/mTOR and MAPK pathways	[33,34,38,39,41,43-45]
10-gingerol	Reduces cell division and induces S-phase cell cycle arrest and apoptosis; exhibits anti-neuroinflammatory and antioxidant activity	AKT decrease, PI3K/p38 MAPK decrease, EGFR increase, NF-кB decrease, AMPK increase, mTOR pathway modulation	[34,36,41]
6-shogaol	Increases antioxidant enzyme levels; inhibits tumor invasion; prevents TNF-α-induced barrier loss	MMP-9 expression decrease, PI3K/AKT decrease, NF-кB decrease, MAPK decrease, Nrf2 increase	[33-35,37]
10-shogaol	Exhibits anti-inflammatory and anti-cancer activity; reduces lipid accumulation	AMPK increase, NF-кB decrease	[33,39,41]
Zingerone	Exhibits antioxidant and anti-inflammatory effects, antiemetic activity and cytoprotective effect	NF-кB decrease, IL-1β decrease, 5-hydroxytryptamine 3 antagonist	[33,34,41,44]
Paradols (6-, 8-, 10-)	Exhibits anti-proliferative, antioxidant, anti-inflammatory activity	PI3K/AKT/mTOR decrease, NF-кB decrease	[39,41,44]
Gingerenone A	Exhibits anti-tumor, pro-apoptotic and anti-inflammatory activity	JAK2/STAT3 decrease	[33,34,40,41]
β-sesquiphellandrene	Exhibits antioxidant, antimicrobial and anti-inflammatory activity	NF-кB decrease, MAPK decrease	[33,41]
Geraniol	Promotes autophagy; exhibits antioxidant activity	AMPK increase, mTOR decrease	[33,34,42]
Phenolic acids (gallic, ferulic, caffeic, ellagic, hydroxybenzoic acid)	Scavenges reactive species; modulates inflammation and lipid metabolism	NF-кB decrease, PI3K/MAPK decrease, AMPK increase, Nrf2/HO-1 increase	[33,41,43]
Minor flavonoids (quercetin, rutin, naringenin)	Exhibits antioxidant and anti-inflammatory activity	NF-кB decrease, Nrf2 increase	[33,41]

NF-кB: Nuclear factor kappa-light-chain-enhancer of activated B cells; STAT: Signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; PI3K/AKT: Phosphatidylinositol 3-kinase/protein kinase B; BAX: BCL2-associated X protein; ROS: Reactive oxygen species; HO-1: Heme oxygenase-1; EGFR: Epidermal growth factor receptor; ERK: Extracellular regulated protein kinases; mTOR: Mechanistic target of rapamycin; TNF-α: Tumor necrosis factor-α; Nrf2: Nuclear factor erythroid 2-related factor 2; MMP: Matrix metalloproteinases; IL-1β: Interleukin-1β; JAK: Janus kinase.

Among these, 6-gingerol and 10-gingerol activate the Nrf2/antioxidant response element pathway and attenuate NF-κB/mitogen-activated protein kinase (MAPK) signaling, thereby restoring antioxidant enzyme activity (superoxide dismutase, catalase, glutathione peroxidase) and reducing lipid peroxidation[33,34]. Shogaols, particularly 6-shogaol and 10-shogaol, show enhanced electrophilic and anti-inflammatory activity: 6-shogaol inhibits NF-κB and signal transducer and activator of transcription 3 (STAT3) and promotes autophagy-linked cytoprotection[35-38], whereas 10-shogaol activates AMPK with favorable effects on lipid metabolism[39]. Zingerone, paradols, and gingerenone A exert complementary actions via phosphoinositide 3-kinase/protein kinase B, Janus kinase/STAT, and toll-like receptor 4 signaling[33,40,41]. Together, these actions provide a coherent mechanistic rationale for the antioxidant and anti-inflammatory outcomes reported in acrylamide-induced hepatotoxicity.

Sesquiterpenes (β-sesquiphellandrene, β-bisabolene), curcumene, and geraniol further contribute to redox balance and membrane stabilization through NF-κB/MAPK and AMPK modulation[42-44]. Likewise, phenolic acids (ferulic, caffeic, ellagic) and flavonoids (quercetin, kaempferol, naringenin) reinforce the Nrf2 axis and suppress pro-inflammatory transcription[45].

Altogether, the concerted activity across Nrf2, NF-κB, MAPK, phosphoinositide 3-kinase/protein kinase B, Janus kinase/STAT, AMPK, and toll-like receptor 4 cascades underlies the biochemical (malondialdehyde decrease; glutathione/superoxide dismutase increase) and histological protection observed by Nour El Deen et al[26]. As noted above, future studies would benefit from full compositional profiling of the extract (e.g., high-performance liquid chromatography standardization ≥ 20% 6-gingerol) and protein-level confirmation of molecular endpoints to strengthen mechanistic attribution (Table 1).

Beyond preclinical data, the translational implications deserve equal emphasis. Randomized controlled trials in non-alcoholic fatty liver disease have shown improvements in liver enzymes (e.g., alanine aminotransferase) and metabolic indices[46], whereas in patients with type 2 diabetes plus non-alcoholic fatty liver disease the benefits are predominantly metabolic[47]. A recent meta-analysis confirmed that ginger supplementation improves glycemic control and reduces oxidative stress in patients with metabolic disorders, indirectly supporting its hepatoprotective potential[48,49]. Extending this evidence to acrylamide-related liver injury underscores the translational relevance of nutraceutical strategies against dietary contaminants.

The findings of Nour El Deen et al[26] are consistent with earlier reports of ginger’s hepatoprotective role in toxicant- and diet-induced injury, including models of carbon tetrachloride, bromobenzene, and high-fat diets[31,50]. More recently, dose- and age-dependent variations in hepatoprotective efficacy have been described[51]. These findings underscore the need to better define optimal dosing regimens. Notable strengths of the study include the use of a chemically defined extract, the integration of molecular, biochemical, and histological endpoints, and the consistency of results across analyses. In addition, the use of a high-performance liquid chromatography-standardized extract ensures pharmacological reproducibility and represents an important step toward evaluating nutraceuticals with the same rigor applied to pharmaceuticals.

Limitations include the short experimental period, which does not mimic chronic human exposure, and the lack of protein-level validation of gene expression. Apoptotic and autophagic pathways, highly relevant in acrylamide hepatotoxicity, were also not assessed. These gaps underscore the need for multidimensional approaches, including multi-omics and proteomic validation, to map ginger’s hepatoprotective actions more comprehensively[52,53]. In addition, the original paper did not provide a complete phytochemical profile of the extract. Table 1 now summarizes this aspect, listing the major phenolic and terpenoid constituents together with their molecular targets and biological effects. Inclusion of such compositional data in future experimental studies will enhance comparability across laboratories and facilitate translational standardization.

TRANSLATIONAL AND PUBLIC HEALTH IMPLICATIONS

The message for hepatologists and public health professionals is twofold. First, acrylamide exposure is ubiquitous and almost unavoidable[54]; its contribution to liver disease, although often overlooked, warrants greater attention. Second, nutraceuticals such as ginger, when rigorously standardized and evaluated, may offer safe, inexpensive, and accessible means of mitigation, particularly in resource-limited settings[55]. In parallel, dietary strategies may also contribute to lowering acrylamide exposure, such as favoring cooking methods with lower thermal intensity (e.g., boiling or steaming instead of frying) and reducing the intake of ultra-processed foods, which remain a major source of acrylamide in Western diets[15,16]. When combined with standardized nutraceutical interventions, such measures form an integrated and pragmatic prevention framework (Figure 1). Biomarker-guided targeting (e.g., AA-Val/GA-Val hemoglobin adducts) could further identify high-risk individuals for stratified prevention with standardized ginger.

Figure 1 Translational framework for acrylamide exposure and prevention. Acrylamide from common foods can trigger oxidative stress, DNA adducts, inflammation, and mitochondrial dysfunction. Monitoring tools (biosensors, omics, risk stratification) and preventive measures (standardized ginger extract, food-processing mitigation) act as complementary pillars; their integration enables stratified prevention and evidence-based public health. CYP2E1: Cytochrome P450 2E1; Nrf2: Nuclear factor erythroid 2-related factor 2; GSH: Glutathione; SOD: Superoxide dismutase; CAT: Catalase; NF-кB: Nuclear factor kappa-light-chain-enhancer of activated B cells.

It should also be recognized that acrylamide is only one of several foodborne electrophilic toxicants. Related compounds, including acrolein, heterocyclic amines, and advanced glycation end-products, share convergent mechanisms (oxidative stress, mitochondrial dysfunction, cytokine activation) that can be counteracted by the multitarget activity of ginger constituents[33,44]. This broader toxicological relevance increases the potential impact of ginger-based nutraceutical approaches in public health. Framing ginger as a harm-reduction tool rather than a dietary panacea is essential. Modest effects at the individual level can translate into meaningful population-level benefits, particularly when combined with exposure-reduction strategies and targeted interventions for vulnerable groups. Future preventive strategies could also explore combinations of nutraceuticals like ginger with established hepatoprotective agents such as silymarin[56], paving the way to synergistic, food-based pharmacology against unavoidable dietary toxins. From an editorial perspective, the broader lesson is that nutraceuticals can indeed move from traditional remedies to credible tools in hepatology, but only if they are studied with the same standards as those applied to pharmaceuticals. In this context, ginger combines strong safety data, cultural acceptability, and multi-target molecular activity, making it a particularly promising candidate. The path forward lies in chronic exposure models and carefully designed clinical trials. For hepatologists, the key takeaway is clear: The same diet may contain both toxin and protector, risk and remedy.

CONCLUSION

Altogether, the study by Nour El Deen et al[26] illustrates how a nutraceutical long rooted in traditional medicine can be repositioned in modern hepatology through biochemical, histological, and molecular rigor. Innovation lies in turning tradition into reproducible, evidence-based prevention, avoiding both uncritical enthusiasm and premature skepticism. Rigorous reporting, standardization, and long-term safety evaluation will determine whether these promising preclinical findings can translate into meaningful public-health outcomes.