Hepatoprotective effects and mechanistic basis of cinnamaldehyde in preclinical liver disease models: A systematic review

Abstract

Objective

To systematically evaluate the preclinical evidence on the hepatoprotective effects of cinnamaldehyde and summarize the key biological mechanisms underlying its actions across different liver disease settings.

Methods

A systematic search was conducted in PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, and Wanfang databases from inception through January 2026. Studies were considered eligible if cinnamaldehyde was used as the main intervention in liver-related disease or injury models and reported at least one liver-relevant outcome was reported. Data extraction and study selection were performed independently by two reviewers. Risk of bias was assessed using RoB 2.0.

Results

A total of 454 records were identified, of which 9 studies met the eligibility criteria for qualitative synthesis. All included studies were preclinical, comprising in vivo, in vitro, or combined designs. The evidence covered liver fibrosis, metabolic liver injury or steatosis, infection-associated liver injury, and hepatic encephalopathy. Across these settings, cinnamaldehyde was consistently associated with improved liver biochemical indices, attenuation of histopathological injury, and reductions in steatosis, collagen deposition, inflammation, oxidative stress, and apoptosis. Mechanistically, the reported effects involved several pathways associated with fibrogenesis, metabolic regulation, inflammatory signaling, and liver–brain axis dysfunction.

Conclusion

Current preclinical evidence supports the use of cinnamaldehyde as a promising hepatoprotective compound with multitarget activity across several liver injury contexts. However, the available data remain limited to experimental studies; therefore, further studies are warranted to clarify its pharmacological profile, cell-specific mechanisms, and translational relevance.

Registration: The protocol was registered with the International Prospective Register of Systematic Reviews database (CRD420261346515).

Keywords

Cinnamaldehyde hepatoprotection liver fibrosis steatosis systematic review

Introduction

The liver is a central organ for metabolism, detoxification, and immune regulation and plays an indispensable role in maintaining systemic physiological homeostasis.¹ Hepatic health directly influences a wide range of biological functions, including energy metabolism, protein synthesis, lipid handling, bile production and secretion, and biotransformation and clearance of drugs and xenobiotics.² Concurrently, the liver is continuously exposed to diverse endogenous and exogenous insults that can precipitate a spectrum of liver disorders, including acute and chronic liver injury, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, cirrhosis, and hepatocellular carcinoma.^3,4 In recent years, the global burden of liver diseases has continued to increase, with the incidence of NAFLD and liver fibrosis rising steadily. According to the World Health Organization (WHO), liver diseases rank as the third leading cause of death worldwide.^5,6 Although a variety of pharmacological agents are currently available for the management of liver disorders, therapeutic progress remains limited by modest efficacy and clinically relevant adverse effects.^7,8 Against this backdrop, there is growing interest in identifying new hepatoprotective interventions from natural sources, particularly plant-derived compounds with relatively low toxicity and broad pharmacological activity.⁹

Cinnamaldehyde (CA) is a naturally occurring aromatic compound extracted primarily from cinnamon bark. Owing to its characteristic fragrance, it has long been used in foods, flavorings, and medicinal preparations.¹⁰ In addition to its role as a flavor constituent, CA has attracted substantial scientific interest due to its broad bioactivity. Experimental studies demonstrated that CA exhibits multiple biological properties, including antioxidant, anti-inflammatory, antimicrobial, antitumor, and antidiabetic effects.¹¹ Notably, CA has shown considerable promise in hepatoprotection through its combined antioxidant, anti-inflammatory, and antifibrotic actions, thereby mitigating liver injury and slowing the progression of hepatic fibrosis.¹² Multiple in vitro and animal studies indicate that CA can attenuate chemically induced liver damage or alcohol-related hepatic injury, improve biochemical indices of liver function, and suppress fibrogenic remodeling.^13,14 Mechanistically, these protective effects presumably involve inhibition of hepatic stellate cell activation, enhancement of endogenous antioxidant defenses, and reduced production of pro-inflammatory mediators.^15,16 However, despite the accumulating preclinical evidence supporting the hepatoprotective potential of CA, the literature remains dominated by cell-based assays and animal models, with relatively limited depth in mechanistic dissection and a paucity of long-term clinical investigations.^17,18 Consequently, key uncertainties persist regarding CA’s precise molecular targets, optimal dosing strategies, clinical indications, and safety profile in humans.

This systematic review aimed to critically synthesize the available preclinical evidence on the hepatoprotective effects of CA, with particular attention to its efficacy across different liver disease settings and the biological mechanisms underlying these effects. By integrating findings from experimental studies, this review sought to clarify the current evidence base regarding the role of CA in liver fibrosis, metabolic liver injury, infection-associated liver injury, and hepatic encephalopathy. Through this approach, we aimed to provide a clearer framework for understanding the pharmacological potential of CA in liver protection, identify the major mechanistic pathways implicated in its actions, and highlight key areas warranting further investigation.

Methods

Study design

This systematic review was conducted in accordance with the principles of the Cochrane Handbook for conducting systematic reviews of interventions. Additionally, it adhered to the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA)¹⁹ and was duly registered with the International Prospective Register of Systematic Reviews (PROSPERO) (Registration Number: CRD420261346515).

Search strategy

An extensive and meticulous investigation was independently conducted by two researchers. This investigation spanned multiple databases from their inception through January 2026, including PubMed, Cochrane, Embase, Web of Science, the China National Knowledge Infrastructure (CNKI), and Wanfang databases. Literature retrieval was performed in both English and Chinese. The search terms applied across all databases are outlined in Supplementary Table 1.

Eligibility criteria

Studies that met the following criteria were eligible for inclusion: (1) CA was used as the main intervention, either in free form or in a formulation in which it remained the principal active component. (2) The study investigated a liver-related disease or injury model, including hepatic steatosis, metabolic dysfunction–associated steatotic liver disease, NAFLD-associated fibrosis, toxic fibrosis, infection-related liver injury, or hepatic encephalopathy with defined hepatic outcomes. (3) The study was performed in animals, cells, or both. (4) At least one liver-relevant outcome was reported, such as liver enzymes, histopathology, steatosis, fibrosis, inflammation, oxidative stress, apoptosis, mitochondrial dysfunction, or other hepatoprotective mechanistic findings.

The exclusion criteria were as follows: (a) studies that were reviews or other non-original articles; (b) studies in which CA was not the primary intervention, or its independent effect could not be distinguished from mixed preparations; (c) studies in which the liver was not the primary focus; (d) pharmacokinetic, toxicological, or general metabolic studies without direct hepatoprotective outcomes; or (e) studies involving animal nutrition, feed additives, poultry, livestock, or aquaculture models.

Data extraction

Initially, two reviewers independently screened studies based on their titles and abstracts to identify articles that met the eligibility criteria. Studies that did not fulfill these criteria were excluded. Subsequently, the full texts of the selected articles were evaluated in detail to assess eligibility and to extract relevant data. Any disagreements were resolved though discussions between the reviewers, leading to a final decision.

Evaluation of bias risk

The methodological quality was evaluated through the use of the Cochrane risk of bias tool for randomized trials, known as RoB 2.0.²⁰ This evaluation included biases arising from the randomization process, deviations from the planned interventions, missing outcome data, outcome measurement, and selection of reported results. Each area was classified as having a low risk of bias, some concerns, or a high risk of bias.

Results

Literature search flow and study selection

A total of 454 records were identified from 6 databases. After removing 187 duplicates, 267 records were screened based on titles and abstracts, of which 202 were excluded. Subsequently, 65 full-text articles were assessed for eligibility. Of these, 56 articles were excluded because they were not liver-focused, did not evaluate CA as the primary intervention, did not report liver-specific outcomes, or were related to animal nutrition/feed additive studies involving poultry, livestock, or aquaculture species. Ultimately, nine studies met the eligibility criteria and were included in this systematic review.^11,21–28 The PRISMA flow diagram is presented in Figure 1.

Figure 1.

Flow chart of study selection.

General characteristics of the included studies

Table 1 summarizes the key characteristics of the studies included in our analysis. Of these, five were exclusively in vivo,^{11,23,24,26,27} three combined in vivo and in vitro experiments,^21,22,25 and one was a purely in vitro mechanistic study.²⁸ The included studies covered a number of liver-associated disease conditions, including liver fibrosis, NAFLD-associated hepatic fibrosis, metabolic dysfunction–associated steatotic liver illness or steatosis, infection-related liver injury, hepatic encephalopathy, and diabetes-associated secondary hepatic damage, among others.

Table 1.

Characteristics of the included studies.

Study (author, year)	Disease context/model	Study type	Intervention characteristics	Main mechanisms and findings
Niu et al.²¹	BDL-induced liver fibrosis; gut–liver axis dysfunction	In vivo + in vitro	Vitamin A–integrated CA nanoemulsion (Va-Cin@NM) compared with free CA	Representative evidence for formulation-enhanced antifibrotic efficacy of CA: Improved liver injury and fibrosis, reduced collagen deposition and stellate cell activation, and alleviated inflammatory/oxidative injury
Gao et al.²²	CCl4-induced liver fibrosis in rats; TGF-β1–stimulated LX2 cells	In vivo + in vitro	Low-/high-dose CA with parallel cellular validation	Core evidence for direct antifibrotic activity of CA: Reduced ALT/AST and fibrosis-related histological damage; decreased α-SMA, collagen I, and TGF-β–associated fibrotic response
Wang et al.¹¹	Salmonella typhimurium–induced infectious liver injury in mice	In vivo	Preventive CA administration before and during infection	Representative evidence for infection-associated hepatoprotection: Reduced ALT/AST, MPO, histological injury, inflammatory cytokines, oxidative stress, and hepatocyte apoptosis; improved survival-related phenotypes
Wu and Xu²³	HFD-induced NAFLD-associated hepatic fibrosis in rats	In vivo	Low-/high-dose CA; additional K6PC-5 reversal group	Key evidence linking CA to metabolic liver injury progression toward fibrosis: Improved lipid profile and liver function, decreased inflammatory cytokines, attenuated steatosis, collagen deposition, and COL1A1 and α-SMA expression
Neto et al.²⁴	Early obesity model with hepatic metabolic dysfunction	In vivo	CA treatment during adolescence with short- and long-term follow-up	Evidence for preventive/metabolic reprogramming effects of CA in obesity-related liver dysfunction: Reduced hepatic lipogenesis and triglyceride accumulation; transient improvement in autophagy and ER stress markers; partial long-term metabolic benefit
Wang et al.²⁵	HFD-induced MASLD in mice; palmitate-treated HepG2 cells; Trpa1 deficiency/antagonism models	In vivo + in vitro	CA as a TRPA1 agonist with knockout/knockdown and antagonist validation	One of the strongest mechanistic studies for CA in MASLD/steatosis: Reduced hepatic steatosis, inflammation and mitochondrial injury; improved lipid accumulation and mitochondrial function in hepatocytes
Abd El Salam et al.²⁶	TAA-induced hepatic encephalopathy in rats	In vivo	CA alone or combined with lactulose	Representative evidence for hepatic encephalopathy/liver–brain axis: Improved ALT/AST, hyperammonemia, liver pathology, oxidative stress and inflammatory injury; also improved brain-related outcomes
Abdelmageed et al.²⁷	STZ/HFD/fructose-induced diabetic liver injury in rats	In vivo	CA treatment in diabetes-associated metabolic injury	Evidence for diabetes-associated secondary hepatic protection by CA: Reduced ALT/AST, hepatic steatosis, oxidative stress and inflammatory changes; improved hepatic pathology
Xu et al.²⁸	FFA-induced hepatocyte steatosis in AML12/HepG2 cells	In vitro	CA treatment with METTL3 knockdown, transcriptomics and metabolomics	Mechanistic cell-level support for CA against steatosis: Reduced lipid accumulation and TG content in steatotic hepatocytes

CA: cinnamaldehyde; BDL: bile duct ligation; Va-Cin@NM: vitamin A–integrated cinnamaldehyde nanoemulsion; CCl4: carbon tetrachloride; TGF-β1: transforming growth factor beta 1; LX2: human hepatic stellate cell line; ALT: alanine aminotransferase; AST: aspartate aminotransferase; α-SMA: alpha-smooth muscle actin; MPO: myeloperoxidase; HFD: high-fat diet; NAFLD: nonalcoholic fatty liver disease; COL1A1: collagen type I alpha 1 chain; ER stress: endoplasmic reticulum stress; MASLD: metabolic dysfunction–associated steatotic liver disease; HepG2: human hepatocellular carcinoma cell line; TRPA1: transient receptor potential ankyrin 1; TAA: thioacetamide; STZ: streptozotocin; FFA: free fatty acid; AML12: alpha mouse liver 12 hepatocyte cell line; METTL3: methyltransferase-like 3; TG: triglyceride; K6PC-5: N-(1,3-dihydroxypropan-2-yl)-2-hexyl-3-oxodecanamide.

In terms of intervention, most studies evaluated free CA as the principal treatment, whereas one study investigated a vitamin A–integrated CA nanoemulsion and another assessed CA alone or in combination with lactulose. The reported outcomes consistently focused on liver-relevant endpoints, including serum liver enzymes, hepatic histopathology, steatosis, collagen deposition, fibrosis-related markers, inflammatory cytokines, oxidative stress indices, apoptosis, and, in some studies, mitochondrial dysfunction or gut–liver axis–related changes. Mechanistically, the included studies suggested that the hepatoprotective effects of CA were associated with several pathways, including CYP2A6/Notch3, SphK1/S1P, TRPA1/AMPK/CPT1A, P2X7R/NLRP3, IRS1/PI3K/AKT2, and METTL3-mediated fatty acid metabolism. Overall, the reviewed studies suggest that CA has been investigated across a broad spectrum of preclinical liver injury models, with the strongest findings observed in fibrosis- and steatosis-related settings.

Risk of bias of the included studies

The risk of bias assessment is presented in Figure 2. Out of the nine studies, seven were rated as having overall low risk of bias, whereas two studies were rated as having some concerns; none were rated as having high risk. In terms of the domain level, all studies were rated as low risk for deviations from intended interventions and missing outcome data. The two studies in the domain randomization process were rated as having some concerns, whereas the rest of the studies were rated as low risk. One study was rated as having some concerns in each domain due to measurement of the outcome and selection of reported result, whereas all other studies were considered low risk. Overall, the risk of bias was low across all studies. However, some uncertainty remained for a few studies, particularly regarding randomization and selected aspects of outcome assessment and reporting.

Figure 2.

Risk of bias assessment.

Effects of CA on liver fibrosis and fibrosis-related progression

Three studies evaluated the effects of CA on liver fibrosis or fibrosis-related progression. In a bile duct ligation model, a vitamin A–integrated CA nanoemulsion reduced collagen deposition and bile duct–like structure proliferation, along with improvement in gut–liver axis–related abnormalities.²¹ A study on a carbon tetrachloride (CCl4)–induced fibrosis model indicated that CA improved liver function in animals and reduced the fibrotic area. Moreover, it downregulated the markers associated with fibrotic activity such as alpha-smooth muscle actin (α-SMA) and collagen I. Additionally, researchers investigated a second system involving transforming growth factor beta 1 (TGF-β1)–stimulated human hepatic stellate cell line (LX2) cells, in which CA inhibited the activation of hepatic stellate cells.²² In a NAFLD-associated fibrosis model, CA alleviated histopathological injury, reduced collagen fiber deposition, lowered collagen type I alpha 1 chain (COL1A1) and α-SMA expression, and improved serum lipid parameters, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and inflammatory cytokines.²³ Overall, the available evidence indicates that CA exerts antifibrotic effects in both direct fibrosis models and fibrosis-related progression associated with metabolic liver disease.

Effects of CA on metabolic liver injury and steatosis

An early obesity model evaluated the impact of CA on the liver and demonstrated decreased lipogenesis and reduced triglyceride deposition. Moreover, short-term improvement of parameters associated with autophagy and endoplasmic reticulum stress was observed.²⁴ In diet-induced metabolic dysfunction–associated steatotic liver disease (MASLD), CA attenuated hepatic steatosis, inflammation, and mitochondrial injury, and similar effects were observed in palmitate-treated hepatocytes.²⁵ In a diabetic rat model, CA decreased ALT and AST. In addition, this compound improved hepatic steatosis and inflammatory injury as well as alleviated oxidative stress.²⁷ The independent in vitro experiment revealed that free fatty acid (FFA)–treated alpha mouse liver 12 hepatocyte cell line (AML12) and human hepatocellular carcinoma cell line (HepG2) demonstrated reduced lipid accumulation following CA treatment.²⁸ Therefore, the aforementioned studies suggest that CA exerts a protective effect against steatosis and metabolic liver injury.

Effects of CA on infection-associated liver injury

One study evaluated CA in Salmonella typhimurium–challenged mice,¹¹ where it alleviated infection-associated liver injury, as indicated by reduced histological damage, lower hepatic myeloperoxidase (MPO) activity, and decreased serum ALT and AST levels. It also suppressed hepatic pro-inflammatory cytokines and chemokines, reduced oxidative stress and hepatocyte apoptosis, and partially corrected infection-related gut microbiota disturbance.

Effects of CA in hepatic encephalopathy

One study investigated CA in a thioacetamide-induced hepatic encephalopathy model.²⁶ CA, either alone or in combination with lactulose, improved liver-related outcomes, including ALT, AST, serum ammonia, liver histopathology, oxidative stress, and hepatic interleukin (IL)-1β levels. This study also demonstrated improvement in brain pathology and behavioral performance. The findings indicate that CA may be beneficial in hepatic encephalopathy, thereby improving hepatic injury and liver–brain axis–related abnormalities.

Discussion

Liver diseases remain a major cause of morbidity and mortality worldwide and encompass a broad spectrum of pathological processes, including fibrosis, metabolic injury, infection-associated damage, and hepatic encephalopathy.²⁹ CA has attracted increasing attention owing to its anti-inflammatory, antioxidant, and metabolic regulatory properties. However, the available evidence has largely been derived from isolated experimental models, making it difficult to define its overall hepatoprotective profile.^30,31 A focused synthesis of the evidence is therefore needed to determine whether the reported benefits of CA reflect a consistent biological effect across different liver disease settings rather than model-specific observations. In the present systematic review, we synthesized results from nine preclinical studies and found that CA exerted protective effects in several liver-related conditions. Although the disease models and outcome measures varied, the direction of the findings was overall consistent, demonstrating improvements in liver-related biochemical parameters, attenuation of histopathological injury, and reductions in steatosis, collagen deposition, inflammatory activation, oxidative stress, and apoptosis. A schematic summary of the main hepatoprotective actions of CA identified in the included studies is presented in Figure 3.

Figure 3.

Schematic representation of the multimechanistic hepatoprotective effects of cinnamaldehyde.

The strongest evidence was observed in fibrosis-related and metabolic liver disease models, where both functional and structural improvement were consistently observed. The fibrosis-related findings are particularly relevant because they suggest that CA influences more than generic liver injury. In the included studies, CA reduced collagen deposition, fibrotic area, and markers of hepatic stellate cell activation. Notably, these effects were observed not only in direct fibrosis models but also in fibrosis associated with metabolic liver disease.^21–23 This pattern is biologically coherent with current models of chronic liver injury, in which persistent hepatocyte stress, inflammatory macrophage activation, and stellate cell–driven matrix remodeling act together to sustain fibrosis progression.^32,33 The pathway-level findings reported in the included studies, including those for CYP2A6/Notch3 and SphK1/S1P, should therefore be interpreted in a broader context: not as isolated molecular findings but as likely representing different points within a shared profibrotic network connecting cellular injury, inflammation, and extracellular matrix (ECM) accumulation.^22,23,32 The analysis of nanoemulsions raises an important translational consideration: improved delivery is not merely a minor pharmaceutical detail but may substantially impact hepatic exposure and the in vivo biological effect of CA.²¹

Hepatocytes are not merely passive targets of injury; in steatotic, toxic, or infectious states; they generate reactive oxygen species, undergo metabolic stress, and release danger signals, cytokines, lipotoxic mediators, and extracellular vesicles that activate Kupffer cells and recruit monocyte-derived macrophages.^34,35 Kupffer cells, in turn, shape the hepatic inflammatory milieu by producing tumor necrosis factor-alpha (TNF-α), IL-1β, chemokines, and other mediators that can amplify hepatocyte injury, although their effects may also support repair depending on context and phenotype.^33,36 This conceptual framework is supported by the included studies, in which CA reduced hepatic cytokine expression, oxidative stress, apoptosis, and histological injury in models where hepatocyte stress and macrophage-driven inflammation are closely linked.^{11,21,23,26,27} In addition, CA enhances nuclear factor erythroid 2–related factor 2 (Nef2) nuclear translocation and phase II detoxifying enzyme expression in HepG2 cells, supporting a direct cytoprotective effect at the hepatocyte level.³⁷ Experimental studies have also demonstrated that CA can inhibit toll-like receptor 4 (TLR4) activation and suppress macrophage inflammatory responses, providing a plausible basis for reduced Kupffer cell–mediated inflammatory amplification during liver injury.^38,39 Collectively, these findings support a working model in which CA acts on both sides of the hepatocyte–Kupffer cell axis, reducing primary hepatocellular stress and dampening macrophage-driven inflammatory signaling.

This hepatocyte–macrophage framework is particularly relevant in metabolic liver disease, where lipotoxic hepatocyte injury, innate immune activation, and mitochondrial dysfunction are closely interconnected. In experimental models of obesity, MASLD, and diabetes, CA reduced steatosis and improved indices of oxidative and inflammatory injury.^24,25,27,28 These findings are consistent with current concepts of MASLD as a disorder sustained not only by hepatocellular lipid overload but also by innate immune activation and interorgan crosstalk.⁴⁰ The mechanistic signals identified in the included studies, including TRPA1/AMPK/CPT1A, IRS1/PI3K/AKT2, and METTL3/CYP4F40, suggest that CA may regulate hepatic lipid handling at multiple levels, including fatty acid oxidation, insulin-responsive signaling, and transcriptional or post-transcriptional control of lipid metabolism.^25,27,28 The infection-associated and hepatic encephalopathy studies further broaden this picture. In the Salmonella model, CA reduced inflammatory signaling, oxidative stress, apoptosis, and microbiota disturbance.¹¹ In hepatic encephalopathy, CA improved liver injury and hyperammonaemia and also attenuated neuroinflammatory changes, suggesting that its effects may extend to the liver–brain axis under conditions of severe hepatic dysfunction.²⁶ Although these observations do not support a single unifying mechanism, they indicate that CA acts on several recurring biological processes that are relevant across different forms of liver injury.

Several limitations should be considered when interpreting these findings. First, all included studies were preclinical, and no eligible human study was identified. Second, there was substantial heterogeneity in disease models, formulations, doses, treatment schedules, and outcome definitions, limiting direct comparison across studies. Finally, several studies used preventive or early-intervention designs; therefore, the current evidence more strongly supports disease attenuation than reversal of established liver injury. The present data support the perspective of CA as a promising preclinical liver disease agent of multitargeted activity. IFuture studies should focus on pharmacokinetics, exposure to the liver, cell-specific mechanism, treatment-oriented designs, and finally clinical testing relevant for the translation of claims.

Conclusion

The available preclinical evidence indicates that CA exerts hepatoprotective effects across several liver disease settings, including fibrosis, metabolic liver injury, infection-associated liver damage, and hepatic encephalopathy. Across the included studies, CA was consistently associated with improved biochemical and histological outcomes, along with reductions in steatosis, collagen deposition, inflammation, oxidative stress, and apoptosis. These findings suggest that CA may act through multiple pathways involved in metabolic dysfunction, fibrogenesis, and inflammatory injury. However, all included studies were experimental, and the heterogeneity in models, interventions, and outcome measures limits the strength of the current evidence. Further well-designed studies are needed to clarify its pharmacological profile, define its cell-specific mechanisms, and determine whether these preclinical findings can be translated into clinically meaningful benefits.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605261447143 - Supplemental material for Hepatoprotective effects and mechanistic basis of cinnamaldehyde in preclinical liver disease models: A systematic review

Supplemental material, sj-pdf-1-imr-10.1177_03000605261447143 for Hepatoprotective effects and mechanistic basis of cinnamaldehyde in preclinical liver disease models: A systematic review by Jueliang Li, Wei Chen, Qianhui Lai and Honglei Zhao in Journal of International Medical Research

Footnotes

Acknowledgments

The authors thank a native English-speaking colleague with academic writing experience for carefully reviewing the language of this manuscript and providing helpful suggestions for improving its clarity and readability.

Author contributions

J. Li designed the study, monitored data collection, and drafted the manuscript; W. Chen and Q. Lai cleaned and analyzed the data; H. Zhao revised the manuscript and provided technical support.

AI tools

During the preparation of the manuscript, language refinement was partially assisted by DeepSeek; all content was reviewed and confirmed by the authors.

Data availability statement

The datasets generated and analyzed during this study are available upon reasonable request from the corresponding author.

Declaration of conflicting interests

The authors have no conflicts of interest, financial or personal, related to this study.

Funding

This research was supported with funding from Shenzhen Science and Technology Program (No: JCYJ20230807150802006), Shenzhen Science and Technology Program (No: KJZD20240903102802003), and Shenzhen Healthcare Research Project (No: 2019-25).

Supplemental material

Supplemental material for this article is available online.

ORCID iD

Honglei Zhao

References

Cheng

Nakib

Perciani

, et al. The immune niche of the liver. Clin Sci (Lond) 2021; 135: 2445–2466.

Trefts

Gannon

Wasserman

DH.

The liver. Current Biology 2017; 27: R1147–R1151.

Asrani

Devarbhavi

Eaton

, et al. Burden of liver diseases in the world. J Hepatol 2019; 70: 151–171.

Parola

Pinzani

Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med 2019; 65: 37–55.

GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2020; 5: 245–266.

Younossi

Koenig

Abdelatif

, et al. Global epidemiology of nonalcoholic fatty liver disease–meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73–84.

Służały

Paśko

Galanty

Natural products as hepatoprotective agents-a comprehensive review of clinical trials. Plants (Basel) 2024; 13: 1985.

Datta

Aggarwal

Sehrawat

, et al. Hepatoprotective effects of natural drugs: current trends, scope, relevance and future perspectives. Phytomedicine 2023; 121: 155100.

Mancak

Altintas

Balaban

, et al. Evidence-based herbal treatments in liver diseases. Hepatol Forum 2024; 5: 50–60.

10.

Peng

Song

, et al. The role and mechanism of cinnamaldehyde in cancer. J Food Drug Anal 2024; 32: 140–154.

11.

Wang

Jia

, et al. Protective effects of cinnamaldehyde on the inflammatory response, oxidative stress, and apoptosis in liver of salmonella typhimurium-challenged mice. Molecules 2021; 26: 2309.

12.

Almoiliqy

Wen

Qaed

, et al. Protective effects of cinnamaldehyde against mesenteric ischemia-reperfusion-induced lung and liver injuries in rats. Oxid Med Cell Longev 2020; 2020: 4196548.

13.

Zhu

Liu

, et al. Cinnamaldehyde in diabetes: a review of pharmacology, pharmacokinetics and safety. Pharmacol Res 2017; 122: 78–89.

14.

Gunawardena

Karunaweera

Lee

, et al. Anti-inflammatory activity of cinnamon (C. zeylanicum and C. cassia) extracts-identification of E-cinnamaldehyde and o-methoxy cinnamaldehyde as the most potent bioactive compounds. Food Funct 2015; 6: 910–919.

15.

Vashisth

Kaushik

Vashisth

, et al. Cinnamaldehyde hydrazone derivatives as potential cathepsin B inhibitors: parallel in-vitro investigation in liver and cerebrospinal fluid. Int J Biol Macromol 2024; 272: 132684.

16.

Xiao

Zhang

, et al. Cinnamaldehyde microcapsules enhance bioavailability and regulate intestinal flora in mice. Food Chem X 2022; 15: 100441.

17.

Vasconcelos

Croda

Simionatto

Antibacterial mechanisms of cinnamon and its constituents: a review. Microb Pathog 2018; 120: 198–203.

18.

Tan

Wang

, et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 2015; 16: 26087–26124.

19.

Page

Moher

Bossuyt

, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ 2021; 372: n160.

20.

Sterne

JAC

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.

21.

Niu

Chang

, et al. Vitamin A-integrated cinnamaldehyde nanoemulsion: a nanotherapeutic approach to counteract liver fibrosis via gut-liver axis modulation. ACS Nano 2025; 19: 10433–10451.

22.

Gao

Zhang

Gao

, et al. Cinnamaldehyde attenuates CCL4-induced liver fibrosis by inhibiting the CYP2A6/Notch3 pathway. Arab J Gastroenterol 2025; 26: 262–271.

23.

Cinnamaldehyde attenuates hepatic fibrosis in NAFLD rats by inhibiting the SphK1/S1P signaling pathway. J Guangzhou Univ Tradit Chin Med 2025; 42: 2288–2294.

24.

Neto

JGO

Boechat

Romão

, et al. Treatment with cinnamaldehyde reduces the visceral adiposity and regulates lipid metabolism, autophagy and endoplasmic reticulum stress in the liver of a rat model of early obesity. J Nutr Biochem 2020; 77: 108321.

25.

Wang

Liu

Wan

, et al. Activation of TRPA1 prevents metabolic dysfunction-associated steatotic liver disease in diet-induced obese mice through stimulating the AMPK/CPT1A signaling pathway. J Physiol Biochem 2025; 81: 359–373.

26.

Abd El Salam

ASG

Abd Elrazik

NA.

Cinnamaldehyde/lactulose combination therapy alleviates thioacetamide-induced hepatic encephalopathy via targeting P2X7R-mediated NLRP3 inflammasome signaling. Life Sci 2024; 344: 122559.

27.

Abdelmageed

Shehatou

Abdelsalam

, et al. Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. Naunyn Schmiedebergs Arch Pharmacol 2019; 392: 243–258.

28.

Xiao

Zhang

, et al. The methyltransferase METTL3-mediated fatty acid metabolism revealed the mechanism of cinnamaldehyde on alleviating steatosis. Biomed Pharmacother 2022; 153: 113367.

29.

Gan

Yuan

Shen

, et al. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10: 33.

30.

Han

Gao

, et al. Cinnamaldehyde: pharmacokinetics, anticancer properties and therapeutic potential (Review). Mol Med Rep 2024; 30: 163.

31.

Silva E Silva Figueiredo

De Oliveira

Dos Reis Ferreira

, et al. Cinnamaldehyde for the treatment of microbial infections: evidence obtained from experimental models. Curr Med Chem 2023; 30: 3506–3526.

32.

Hammerich

Tacke

Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol 2023; 20: 633–646.

33.

Krenkel

Tacke

Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 2017; 17: 306–321.

34.

Zhou

Wang

, et al. Crosstalk between liver macrophages and surrounding cells in nonalcoholic steatohepatitis. Front Immunol 2020; 11: 1169.

35.

Carranza-Trejo

Vetvicka

Vistejnova

, et al. Hepatocyte and immune cell crosstalk in non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2021; 15: 783–796.

36.

Zhao

Liu

, et al. Kupffer cells, the limelight in the liver regeneration. Int Immunopharmacol 2025; 146: 113808.

37.

Huang

Chung

, et al. Cinnamaldehyde enhances Nrf2 nuclear translocation to upregulate phase II detoxifying enzyme expression in HepG2 cells. J Agric Food Chem 2011; 59: 5164–5171.

38.

Youn

Lee

Choi

, et al. Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem Pharmacol 2008; 75: 494–502.

39.

Kim

Lee

, et al. Regulatory effect of cinnamaldehyde on monocyte/macrophage-mediated inflammatory responses. Mediators Inflamm 2010; 2010: 529359.

40.

Meyer

Schwärzler

Jukic

, et al. Innate immunity and MASLD. Biomolecules 2024; 14: 476.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.13 MB