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Sadeghi-Nodoushan F, Sasanfar B, Salehi-Abargouei A. Reconsidering the Metabolic Effects of TBHQ: An Overlooked Interaction between Dietary Antioxidants, Lipid Metabolism, and Inflammatory Pathways. JNFS 2026; 11 (3) :331-334
URL: http://jnfs.ssu.ac.ir/article-1-1592-en.html
URL: http://jnfs.ssu.ac.ir/article-1-1592-en.html
Nutrition Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Keywords: TBHQ, dietary antioxidants, lipid metabolism, inflammatory pathways, metabolic syndrome, oxidative stress
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1 Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 2 Department of Laboratory Sciences, School of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;
3 Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;
4 Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran.5 Nutrition Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 6 School of Nutrition and Food Sciences، Shiraz University of Medical Sciences, Shiraz, Iran; 6 Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 7 Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Reconsidering the Metabolic Effects of TBHQ: An Overlooked Interaction between Dietary Antioxidants, Lipid Metabolism, and Inflammatory Pathways
Fateme Sadeghi-Nodoushan; MSc 1-3, Bahareh Sasanfar; PhD 4 & Amin Salehi-Abargouei; PhD *5-7
Fateme Sadeghi-Nodoushan; MSc 1-3, Bahareh Sasanfar; PhD 4 & Amin Salehi-Abargouei; PhD *5-7
1 Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 2 Department of Laboratory Sciences, School of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;
3 Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;
4 Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran.5 Nutrition Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 6 School of Nutrition and Food Sciences، Shiraz University of Medical Sciences, Shiraz, Iran; 6 Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 7 Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| ARTICLE INFO | ||
| EDITORIAL ARTICLE | *Corresponding author abargouei@sums.ac.ir School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran. Postal code: 7153675541 Tel: +:+98 71-317267056 |
|
| Article history: Received: 12 Feb 2026 Revised: 18 May 2026 Accepted: 8 Jul 2026 |
Dear Editor
In recent years, there has been increasing attention on the role of dietary antioxidants in the prevention and modulation of metabolic disorders, particularly metabolic syndrome (MetS). While natural antioxidants have consistently demonstrated beneficial metabolic effects, not much is known about the long-term metabolic consequences of synthetic antioxidants used in food processing. Among these, tertiary butylhydroquinone (TBHQ) is widely incorporated into edible oils to prevent lipid oxidation and prolong shelf life. Despite its technological advantages, the biological relevance of TBHQ exposure to metabolic health remains poorly characterized.
Beyond its established technological role as a synthetic antioxidant added to edible oils to prevent oxidative deterioration, TBHQ has been shown to exert biological activity at the cellular level. Experimental evidence indicates that TBHQ activates the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway, thereby influencing redox balance and phase II detoxification processes (Liu et al., 2023, Ma et al., 2025). Although Nrf2 activation is generally cytoprotective, emerging evidence suggests that sustained or excessive activation may disrupt metabolic homeostasis, particularly in organs central to lipid and glucose regulation. This dual and context-dependent nature of Nrf2 signaling cytoprotective under physiological conditions which is potentially disruptive when chronically activated, raises important questions regarding the long-term metabolic implications of sustained TBHQ exposure (Gumeni et al., 2023, Singh and Chadha, 2024). Indeed, while TBHQ can induce phase II detoxification enzymes through Nrf2-dependent mechanisms, chronic exposure has also been associated with pro-oxidant effects and potential carcinogenicity, partly through the formation of reactive metabolites and GSH conjugates (Gharavi et al., 2007, Xu et al., 2021). Furthermore, TBHQ has been reported to modulate additional signaling pathways, including NF-κB, PI3K/AKT, Wnt, and Hedgehog pathways, underscoring its pleiotropic and context-dependent biological actions (Whisel and Rice, 2025, Zhao et al., 2020, Zhu et al., 2021).
These mechanistic considerations are particularly relevant in the context of MetS, a condition characterized by dyslipidemia, insulin resistance, and chronic low-grade inflammation. Experimental studies suggest that TBHQ may influence key regulators of lipid metabolism, including peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs) (Mika et al., 2023). Alterations in these pathways could plausibly affect circulating lipid parameters such as triglycerides and low-density lipoprotein cholesterol. However, direct evidence from long-term human clinical studies is scarce, and existing data are largely extrapolated from short-term experimental models or heterogeneous dietary contexts (Esazadeh et al., 2024, Shintyapina et al., 2017). To date, no well-controlled, long-term human clinical trials have systematically evaluated the metabolic effects of habitual dietary TBHQ exposure. This gap underscores the need for carefully designed human studies that account for dose, duration, metabolic status, genetic background, and overall dietary composition.
In addition to lipid regulation, TBHQ may influence inflammatory pathways that are central to MetS pathophysiology. Pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute to insulin resistance and atherosclerotic progression. Moreover, redox-sensitive signaling mechanisms provide a plausible link between TBHQ exposure and inflammatory modulation (Awali et al., 2026). Notably, reported effects vary depending on dose, duration of exposure, and metabolic context. For example, tBHQ has been shown to activate MAPK pathways including JNK, ERK, and p38in a time and dose-dependent manner, with oxidative stress contributing to ERK activation (Yu et al., 1997). Such mechanistic complexity, involving both Nrf2-dependent and Nrf2-independent pathways, may explain the divergent findings reported across experimental systems.
An additional and largely underexplored dimension is inter-individual variability in response to TBHQ. Genetic polymorphisms in genes involved in lipid metabolism (e.g., APOA5, LDLR), inflammatory regulation (e.g., IL6), and adipokine signaling (e.g., ADIPOQ) may significantly modify metabolic responses to dietary exposures. Also, gene diet interactions are increasingly recognized as determinants of cardiometabolic risk (Curti et al., 2012, Duarte et al., 2025); however, their potential role in modulating susceptibility to TBHQ exposure has not been adequately investigated. For instance, the well-characterized rs662799 polymorphism in the APOA5 gene influences triglyceride responses to dietary fat intake, providing a biologically plausible framework for differential metabolic responses to TBHQ-containing oils (de Luis et al., 2021).
Moreover, the metabolic effects of TBHQ-containing oils should be interpreted in comparison with those of oils naturally rich in bioactive compounds, such as polyphenols and tocopherols. Natural oil matrices may exert synergistic antioxidant and anti-inflammatory effects that differ fundamentally from those of isolated synthetic additives. Distinguishing the intrinsic properties of the oil from the effects of added TBHQ is therefore essential for accurately evaluating metabolic outcomes.
Given the widespread consumption of TBHQ-containing oils, particularly through processed foods, the current lack of robust human data represents a notable gap in nutritional and metabolic research. Future studies should prioritize well-designed clinical trials with sufficient duration, standardized dietary interventions, and comprehensive metabolic and inflammatory profiling. Integrating genetic analyses may further clarify the mechanisms underlying inter-individual differences in response to TBHQ.
In conclusion, although TBHQ remains an effective food preservative, its broader metabolic implications warrant more systematic and translational investigation. A comprehensive framework integrating redox biology, lipid metabolism, inflammatory signaling, and
gene–diet interactions is essential not only to clarify the role of TBHQ in metabolic syndrome, but also to refine current paradigms of dietary risk assessment in the context of chronic exposure. Incorporating inter-individual genetic variability into such evaluations may further align future research with emerging principles of precision nutrition, particularly in populations at elevated cardiometabolic risk.
Authors’ contributions
All authors contributed to the conceptualization and writing of the manuscript.
Conflicts of interest
The authors declared no conflicts of interest.
Funding
No specific funding was received for this work.
References
Awali S, Jin Y, Duriancik DM & Rockwell CE 2026. The Nrf2 activator tBHQ inhibits dendritic cell maturation and activation in response to bacterial and viral stimuli. Toxicology in vitro. 111: 106169.
Curti ML, et al. 2012. Associations of the TNF-alpha-308 G/A, IL6-174 G/C and AdipoQ 45 T/G polymorphisms with inflammatory and metabolic responses to lifestyle intervention in Brazilians at high cardiometabolic risk. Diabetology & metabolic syndrome. 4 (1): 49.
de Luis D, Izaola O & Primo D 2021. APOA‐5 genetic variant rs662799: role in lipid changes and insulin resistance after a Mediterranean diet in caucasian obese subjects. Disease markers. 2021 (1): 1257145.
Duarte GBS, Pascoal GdFL & Rogero MM 2025. Polymorphisms involved in insulin resistance and metabolic inflammation: Influence of nutrients and dietary interventions. Metabolites. 15 (4): 245.
Esazadeh K, et al. 2024. Cytotoxic and genotoxic effects of tert‐butylhydroquinone, butylated hydroxyanisole and propyl gallate as synthetic food antioxidants. Food science nutrition. 12 (10): 7004-7016.
Gharavi N, Haggarty S & S El-Kadi AO 2007. Chemoprotective and carcinogenic effects of tert-butylhydroquinone and its metabolites. Current drug metabolism. 8 (1): 1-7.
Gumeni S, Lamprou M, Evangelakou Z, Manola MS & Trougakos IP 2023. Sustained Nrf2 overexpression-induced metabolic deregulation can be attenuated by modulating insulin/insulin-like growth factor signaling. Cells. 12 (22): 2650.
Liu X, Yang L, Zhang G & Ling J 2023. Neuroprotective effects of phenolic antioxidant tert-butylhydroquinone (tBHQ) in brain diseases. Molecular neurobiology. 60 (9): 4909-4923.
Ma J, et al. 2025. Tertiary butylhydroquinone regulates oxidative stress in spleen injury induced by gas explosion via the Nrf2/HO-1 signaling pathway. Scientific reports. 15 (1): 11987.
Mika M, Antończyk A, Wikiera A & Sciences N 2023. Influence of synthetic antioxidants used in food technology on the bioavailability and metabolism of lipids-in vitro studies. Polish journal of food. 73 (1): 95-107.
Shintyapina AB, Vavilin VA, Safronova OG & Lyakhovich VV 2017. The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl) propylthiosulfonate of sodium. PLoS One. 12 (5): e0176939.
Singh M & Chadha P 2024. Gastrointestinal toxicity following sub‐acute exposure of erythrosine in rats: biochemical, oxidative stress, DNA damage and histopathological studies. Journal of biochemical molecular toxicology. 38 (11): e70007.
Whisel AM & Rice CD 2025. Tert-butylhydroquinone (TBHQ) suppresses lps-and poly (I: C)-induced RAW 264.7 macrophage activation through reduced NF-κB/type 1 interferon and enhanced antioxidant-related pathways. Toxics. 13 (10): 883.
Xu X, et al. 2021. Synthetic phenolic antioxidants: Metabolism, hazards and mechanism of action. Food chemistry. 353: 129488.
Yu R, Tan T-H & Kong A-NT 1997. Butylated Hydroxyanisole and Its Metabolitetert-Butylhydroquinone Differentially Regulate Mitogen-activated Protein Kinases: The role of oxidative stress in the activation of mitogen-activated protein kinases by phenolic antioxidants. Journal of biological chemistry. 272 (46): 28962-28970.
Zhao Y-L, Zhao W, Liu M, Liu L & Wang YJ 2020. TBHQ‐overview of multiple mechanisms against oxidative stress for attenuating methamphetamine‐induced neurotoxicity. Oxidative medicine cellular longevity. 2020 (1): 8874304.
Zhu T-t, et al. 2021. Tertiary butylhydroquinone alleviated liver steatosis and increased cell survival via β-arrestin-2/PI3K/AKT pathway. Iranian journal of basic medical sciences. 24 (10): 1428.
In recent years, there has been increasing attention on the role of dietary antioxidants in the prevention and modulation of metabolic disorders, particularly metabolic syndrome (MetS). While natural antioxidants have consistently demonstrated beneficial metabolic effects, not much is known about the long-term metabolic consequences of synthetic antioxidants used in food processing. Among these, tertiary butylhydroquinone (TBHQ) is widely incorporated into edible oils to prevent lipid oxidation and prolong shelf life. Despite its technological advantages, the biological relevance of TBHQ exposure to metabolic health remains poorly characterized.
Beyond its established technological role as a synthetic antioxidant added to edible oils to prevent oxidative deterioration, TBHQ has been shown to exert biological activity at the cellular level. Experimental evidence indicates that TBHQ activates the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway, thereby influencing redox balance and phase II detoxification processes (Liu et al., 2023, Ma et al., 2025). Although Nrf2 activation is generally cytoprotective, emerging evidence suggests that sustained or excessive activation may disrupt metabolic homeostasis, particularly in organs central to lipid and glucose regulation. This dual and context-dependent nature of Nrf2 signaling cytoprotective under physiological conditions which is potentially disruptive when chronically activated, raises important questions regarding the long-term metabolic implications of sustained TBHQ exposure (Gumeni et al., 2023, Singh and Chadha, 2024). Indeed, while TBHQ can induce phase II detoxification enzymes through Nrf2-dependent mechanisms, chronic exposure has also been associated with pro-oxidant effects and potential carcinogenicity, partly through the formation of reactive metabolites and GSH conjugates (Gharavi et al., 2007, Xu et al., 2021). Furthermore, TBHQ has been reported to modulate additional signaling pathways, including NF-κB, PI3K/AKT, Wnt, and Hedgehog pathways, underscoring its pleiotropic and context-dependent biological actions (Whisel and Rice, 2025, Zhao et al., 2020, Zhu et al., 2021).
These mechanistic considerations are particularly relevant in the context of MetS, a condition characterized by dyslipidemia, insulin resistance, and chronic low-grade inflammation. Experimental studies suggest that TBHQ may influence key regulators of lipid metabolism, including peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs) (Mika et al., 2023). Alterations in these pathways could plausibly affect circulating lipid parameters such as triglycerides and low-density lipoprotein cholesterol. However, direct evidence from long-term human clinical studies is scarce, and existing data are largely extrapolated from short-term experimental models or heterogeneous dietary contexts (Esazadeh et al., 2024, Shintyapina et al., 2017). To date, no well-controlled, long-term human clinical trials have systematically evaluated the metabolic effects of habitual dietary TBHQ exposure. This gap underscores the need for carefully designed human studies that account for dose, duration, metabolic status, genetic background, and overall dietary composition.
In addition to lipid regulation, TBHQ may influence inflammatory pathways that are central to MetS pathophysiology. Pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute to insulin resistance and atherosclerotic progression. Moreover, redox-sensitive signaling mechanisms provide a plausible link between TBHQ exposure and inflammatory modulation (Awali et al., 2026). Notably, reported effects vary depending on dose, duration of exposure, and metabolic context. For example, tBHQ has been shown to activate MAPK pathways including JNK, ERK, and p38in a time and dose-dependent manner, with oxidative stress contributing to ERK activation (Yu et al., 1997). Such mechanistic complexity, involving both Nrf2-dependent and Nrf2-independent pathways, may explain the divergent findings reported across experimental systems.
An additional and largely underexplored dimension is inter-individual variability in response to TBHQ. Genetic polymorphisms in genes involved in lipid metabolism (e.g., APOA5, LDLR), inflammatory regulation (e.g., IL6), and adipokine signaling (e.g., ADIPOQ) may significantly modify metabolic responses to dietary exposures. Also, gene diet interactions are increasingly recognized as determinants of cardiometabolic risk (Curti et al., 2012, Duarte et al., 2025); however, their potential role in modulating susceptibility to TBHQ exposure has not been adequately investigated. For instance, the well-characterized rs662799 polymorphism in the APOA5 gene influences triglyceride responses to dietary fat intake, providing a biologically plausible framework for differential metabolic responses to TBHQ-containing oils (de Luis et al., 2021).
Moreover, the metabolic effects of TBHQ-containing oils should be interpreted in comparison with those of oils naturally rich in bioactive compounds, such as polyphenols and tocopherols. Natural oil matrices may exert synergistic antioxidant and anti-inflammatory effects that differ fundamentally from those of isolated synthetic additives. Distinguishing the intrinsic properties of the oil from the effects of added TBHQ is therefore essential for accurately evaluating metabolic outcomes.
Given the widespread consumption of TBHQ-containing oils, particularly through processed foods, the current lack of robust human data represents a notable gap in nutritional and metabolic research. Future studies should prioritize well-designed clinical trials with sufficient duration, standardized dietary interventions, and comprehensive metabolic and inflammatory profiling. Integrating genetic analyses may further clarify the mechanisms underlying inter-individual differences in response to TBHQ.
In conclusion, although TBHQ remains an effective food preservative, its broader metabolic implications warrant more systematic and translational investigation. A comprehensive framework integrating redox biology, lipid metabolism, inflammatory signaling, and
gene–diet interactions is essential not only to clarify the role of TBHQ in metabolic syndrome, but also to refine current paradigms of dietary risk assessment in the context of chronic exposure. Incorporating inter-individual genetic variability into such evaluations may further align future research with emerging principles of precision nutrition, particularly in populations at elevated cardiometabolic risk.
Authors’ contributions
All authors contributed to the conceptualization and writing of the manuscript.
Conflicts of interest
The authors declared no conflicts of interest.
Funding
No specific funding was received for this work.
References
Awali S, Jin Y, Duriancik DM & Rockwell CE 2026. The Nrf2 activator tBHQ inhibits dendritic cell maturation and activation in response to bacterial and viral stimuli. Toxicology in vitro. 111: 106169.
Curti ML, et al. 2012. Associations of the TNF-alpha-308 G/A, IL6-174 G/C and AdipoQ 45 T/G polymorphisms with inflammatory and metabolic responses to lifestyle intervention in Brazilians at high cardiometabolic risk. Diabetology & metabolic syndrome. 4 (1): 49.
de Luis D, Izaola O & Primo D 2021. APOA‐5 genetic variant rs662799: role in lipid changes and insulin resistance after a Mediterranean diet in caucasian obese subjects. Disease markers. 2021 (1): 1257145.
Duarte GBS, Pascoal GdFL & Rogero MM 2025. Polymorphisms involved in insulin resistance and metabolic inflammation: Influence of nutrients and dietary interventions. Metabolites. 15 (4): 245.
Esazadeh K, et al. 2024. Cytotoxic and genotoxic effects of tert‐butylhydroquinone, butylated hydroxyanisole and propyl gallate as synthetic food antioxidants. Food science nutrition. 12 (10): 7004-7016.
Gharavi N, Haggarty S & S El-Kadi AO 2007. Chemoprotective and carcinogenic effects of tert-butylhydroquinone and its metabolites. Current drug metabolism. 8 (1): 1-7.
Gumeni S, Lamprou M, Evangelakou Z, Manola MS & Trougakos IP 2023. Sustained Nrf2 overexpression-induced metabolic deregulation can be attenuated by modulating insulin/insulin-like growth factor signaling. Cells. 12 (22): 2650.
Liu X, Yang L, Zhang G & Ling J 2023. Neuroprotective effects of phenolic antioxidant tert-butylhydroquinone (tBHQ) in brain diseases. Molecular neurobiology. 60 (9): 4909-4923.
Ma J, et al. 2025. Tertiary butylhydroquinone regulates oxidative stress in spleen injury induced by gas explosion via the Nrf2/HO-1 signaling pathway. Scientific reports. 15 (1): 11987.
Mika M, Antończyk A, Wikiera A & Sciences N 2023. Influence of synthetic antioxidants used in food technology on the bioavailability and metabolism of lipids-in vitro studies. Polish journal of food. 73 (1): 95-107.
Shintyapina AB, Vavilin VA, Safronova OG & Lyakhovich VV 2017. The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl) propylthiosulfonate of sodium. PLoS One. 12 (5): e0176939.
Singh M & Chadha P 2024. Gastrointestinal toxicity following sub‐acute exposure of erythrosine in rats: biochemical, oxidative stress, DNA damage and histopathological studies. Journal of biochemical molecular toxicology. 38 (11): e70007.
Whisel AM & Rice CD 2025. Tert-butylhydroquinone (TBHQ) suppresses lps-and poly (I: C)-induced RAW 264.7 macrophage activation through reduced NF-κB/type 1 interferon and enhanced antioxidant-related pathways. Toxics. 13 (10): 883.
Xu X, et al. 2021. Synthetic phenolic antioxidants: Metabolism, hazards and mechanism of action. Food chemistry. 353: 129488.
Yu R, Tan T-H & Kong A-NT 1997. Butylated Hydroxyanisole and Its Metabolitetert-Butylhydroquinone Differentially Regulate Mitogen-activated Protein Kinases: The role of oxidative stress in the activation of mitogen-activated protein kinases by phenolic antioxidants. Journal of biological chemistry. 272 (46): 28962-28970.
Zhao Y-L, Zhao W, Liu M, Liu L & Wang YJ 2020. TBHQ‐overview of multiple mechanisms against oxidative stress for attenuating methamphetamine‐induced neurotoxicity. Oxidative medicine cellular longevity. 2020 (1): 8874304.
Zhu T-t, et al. 2021. Tertiary butylhydroquinone alleviated liver steatosis and increased cell survival via β-arrestin-2/PI3K/AKT pathway. Iranian journal of basic medical sciences. 24 (10): 1428.
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Received: 2026/02/12 | Published: 2026/08/19 | ePublished: 2026/08/19
Received: 2026/02/12 | Published: 2026/08/19 | ePublished: 2026/08/19
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