Microplastics and nanoplastics: Emerging drivers of liver damage and metabolic dysfunction

Abstract

Advanced liver disease, including cirrhosis and hepatocellular carcinoma (HCC), represents a major global health challenge, driven in part by the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). In parallel, micro-and nanoplastics (MNPs) have emerged as pervasive environmental contaminants with potential hepatotoxic effects. This review provides an in-depth analysis of current knowledge regarding the role of MNPs in the pathogenesis of cirrhosis and HCC, particularly in the context of the growing MASLD burden, and identifies key areas for future research. The literature search included original studies and review articles indexed in PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar from January 1, 2014, to November 1, 2024. Evidence from animal models indicates that MNP exposure may induce hepatic changes resembling those seen in human MASLD and metabolic dysfunction-associated steatohepatitis (MASH) through both direct and indirect mechanisms. Importantly, MNPs may act as a “second hit” in the presence of pre-existing metabolic stress, potentially exacerbating liver injury. However, human data remain scarce, with only two small-scale studies investigating MNPs in clinical cohorts. Recent advances in analytical methods for quantifying MNPs in blood present new opportunities to explore their association with MASLD, cirrhosis, and HCC in human populations. While significant progress has been made in understanding MNP-induced hepatotoxicity in experimental models, their clinical relevance to human liver disease progression remains largely unexplored. Further multidisciplinary research integrating environmental science, molecular biology, and clinical hepatology is urgently needed.

Introduction

Advanced liver disease, encompassing cirrhosis and hepatocellular carcinoma (HCC), represents a significant global health burden, accounting for approximately 4% of all deaths worldwide^[1]—about 1 million fatalities annually.^[2] Cirrhosis, characterized by extensive fibrosis and nodule formation, disrupts the normal hepatic lobular architecture and progressively leads to liver decompensation, manifesting as ascites, hepatic encephalopathy, and variceal hemorrhage.^[3] This condition ranks among the leading causes of mortality globally, holding the fifth position in the Eastern Mediterranean region, ninth in both Southeast Asia and Europe, and tenth in Africa.^[1] Moreover, cirrhosis markedly increases the risk of HCC—the most common form of primary liver cancer and the third leading cause of cancer-related mortality worldwide.^[4,5] The annual incidence of HCC in patients with cirrhosis ranges from 0.2% to 5%, underscoring the need for pathophysiology-informed monitoring and prevention strategies.^[6]

The etiology of advanced liver diseases has evolved substantially over time.^[7] Expanded hepatitis B virus vaccination coverage and the advent of highly effective antiviral therapies have led to a decline in viral hepatitis–related advanced chronic liver disease.^[8] Conversely, epidemiological data reveal a marked increase in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD-related cirrhosis and HCC.^[9,10] MASLD has now become the leading indication for liver transplantation in developed countries.^[10] Its global prevalence—reaching up to 50% and increasingly affecting younger adults—warrants serious concern.^[11–14] Even among liver transplant recipients, MASLD remains highly prevalent, with rates exceeding 30%, suggesting a disease burden comparable to that observed prior to transplantation.^[15] MASLD is also a recognized issue in other transplant populations, including kidney transplant recipients,^[16] and is increasingly among the leading causes for referral to tertiary hepatology centers.^[17] Notably, MASLD maypromote hepatocarcinogenesis even in non-cirrhotic livers, highlighting the need to further investigate its underlying mechanisms.^[18–20]

In this evolving epidemiological context, microand nanoplastics (MNPs) have emerged as a novel environmental risk factor with potential implications for liver health.^[21–25] The ubiquitous presence of persistent plastic particles—in air, drinking water, and food^[26]—together with their capacity to bioaccumulate in hepatic tissue, necessitates a comprehensive assessment of their role in advanced liver disease pathogenesis.^[27,28] In this narrative review, we provide a critical synthesis of current evidence on the potential role of MNPs in the development of cirrhosis and HCC, particularly in light of the rising incidence of MASLD.^[8] By consolidating available findings and identifying major knowledge gaps, we aim to highlight priority areas for future research.

Materials and Methods

For this review, the search strategy (Table 1) included original studies and review articles indexed in PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar between January 1, 2014, and November 1, 2024. This timeframe was chosen to capture the most relevant research published over the past decade.

Table 1.

Search strategy

Variable	Specification
Search date	November 1, 2024
Databases	PubMed/MEDLINE, Web of Science, Scopus, Google Scholar
Search terms	“microplastics,” “nanoplastics,” “liver,” “hepatic,” “metabolic dysfunction-associated steatotic liver disease,” “non-alcoholic fatty liver disease,” “advanced liver disease,” “cirrhosis,” and “hepatocellular carcinoma”
Timeframe	January 1, 2014, to November 1, 2024
Inclusion and exclusion criteria	Inclusion: original studies, review articles; Exclusion: case reports, conference abstracts, articles not published in the English language
Selection process	Preliminary screening of titles and abstracts, followed by full-text screening and narrative synthesis of key data extracted from eligible studies.

The search terms used were: “microplastics,” “nanoplastics,” “liver,” “hepatic,” “metabolic dysfunction-associated steatotic liver disease,” “non-alcoholic fatty liver disease,” “advanced liver disease,” “cirrhosis,” and “hepatocellular carcinoma.” To maintain quality and relevance, case reports, conference abstracts, and non–English-language publications were excluded.

Results

Classification and Composition of Micronanoplastics

A precise classification of MNPs (Fig. 1) is essential for understanding their biological effects and underlying toxicological mechanisms. Broadly, these synthetic particles are categorized into primary and secondary types based on their origin.^[29]

Figure 1.

Classification of micronanoplastics [Created with Biorender.com].

Primary MNPs are intentionally manufactured or arise as byproducts of industrial processes. They include abrasive materials, injection-molding powders, and resin pellets,^[29] and may also be generated through mechanical degradation during the production, use, or maintenance of plastic products.

Secondary MNPs—which constitute the majority of environmental particles and are of greater health concern—result from the gradual degradation of larger plastic items such as packaging, containers, and disposable products. Their release occurs via mechanical abrasion, ultraviolet (UV) radiation, and chemical decomposition, which together fragment larger debris into microscopic particles.^[29]

By size, MNPs are typically classified into:

• Microplastics: 5 mm to 1 μm

• Submicroplastics: 1 μm to 100 nm

• Nanoplastics: <100 nm^[30]

Particle size strongly influences biological interactions, with smaller particles—particularly those at the nanoscale—more readily crossing biological barriers and penetrating cells.^[31]

Chemically, the most frequently detected polymers in environmental MNPs include polyethylene (PE), polypropylene (PP), polyoxymethy-lene (POM), polyethylene terephthalate (PET), polystyrene (PS), polyvinyl chloride (PVC), and polymethyl methacrylate (PMMA).^[31] MNPs also often contain chemical additives—such as plasticizers, lubricants, fillers, UV stabilizers, pigments, dyes, and flame retardants—added during manufacturing to enhance mechanical strength, color, transparency, and performance.^[32]

Beyond their inherent chemical toxicity, MNPs can adsorb a wide variety of microorganisms and hazardous compounds, including persistent organic pollutants. This is due to their hydrophobic surfaces and high surface area-to-volume ratio.^[33] This “Trojan horse” effect enables MNPs to facilitate the bioaccumulation and bioconcentration of chemical toxicants, thereby amplifying their harmful effects on the liver and other organs.^[34]

The Liver as the Target of Micronanoplastics: Direct and Indirect Hepatotoxic Damage

The most compelling evidence for the potential hepatotoxicity of MNPs in humans comes from a pilot study by Horvatits et al.,^[28] which found significantly higher MNP concentrations in liver tissue from patients with cirrhosis (n=6) compared with those without liver disease (n=5). Notably, the latter group tested negative despite rigorous analysis using chemical digestion, staining, fluorescence microscopy, and Raman spectroscopy. Although the authors did not distinguish between primary and secondary MNPs, the surface degradation of some particles suggested the presence of secondary MNPs formed from the breakdown of larger plastic items.^[28,29] The detected microplastics ranged from 4 to 30 μm—within the microplastic size range (5 mm to 1 μm)—and were capable of crossing biological barriers.^[30] Chemical analysis identified six polymer types: PS, PVC, PET, PMMA, POM, and PP.

Several recent reviews,^[21,22,25] which this article does not aim to duplicate, have described in detail the direct and indirect mechanisms by which MNPs may cause hepatotoxicity. Briefly, based largely on preclinical animal studies, these mechanisms can be categorized as either direct or indirect (Fig. 2).

Figure 2.

Schematic representation of the direct and indirect mechanisms of hepatotoxicity induced by micronanoplastics. The indirect effect occurs through gut dysbiosis, characterized by an imbalance in gut microbiota. This leads to the translocation of endotoxins via the portal vein to the liver, resulting in hepatic inflammation. Direct effects include oxidative stress, inflammation, mitochondrial dysfunction, activation of hepatic stellate cells, bile acid disruption, and immunotoxicity [Created with Biorender.com].

Direct hepatotoxic mechanisms include the induction of oxidative stress,^[35] inflammation,^[36] mitochondrial dysfunction,^[37] hepatic stellate cell activation,^[38] disruption of bile acid metabolism,^[39] and immunotoxicity.^[40] Reactive oxygen species generated by MNPs can lead to protein oxidative carbonylation, membrane damage, DNA strand breaks, and ultimately apoptosis, pyroptosis, or other forms of cell death.^[41] Plastic particle–induced cytokine and chemokine expression in hepatic tissue may produce morphological changes resembling those seen in human metabolic dysfunction-associated steatohepatitis (MASH).^[42] MNPs can impair mitochondrial function, adversely affecting hepatocyte energy metabolism due to mitochondria’s critical roles in ATP production and ion homeostasis.^[37,43] They may also activate hepatic stellate cells, promoting excessive extracellular matrix deposition, fibroblast proliferation, and increased hepatic vascular resistance.^[27,38] Direct disruption of bile acid metabolism may result in cholestatic injury, while effects on Kupffer cells—the liver’s resident macrophages—may weaken defenses against lipopolysaccharide (LPS) from gut Gram-negative bacteria entering via the portal vein.^[39]

Indirect hepatotoxic effects are primarily linked to MNP accumulation in the gastrointestinal tract and their impact on gut microbiota composition.^[21,44–47] These changes often include an increase in harmful bacteria, a decrease in beneficial species, and reduced microbial diversity. ^[21,48] MNPs can disrupt key bacterial metabolic pathways, reducing the synthesis of beneficial postbiotics such as short-chain fatty acids.^[49] Microbiota disruption may also compromise intestinal barrier integrity, causing hyperpermeability and translocation of bacteria and their harmful structural or metabolic products into the liver parenchyma.^[50]

Micronanoplastics and MASLD

MASLD is a multisystem disease that extends beyond the liver. Its pathogenesis involves multiple contributing factors, consistent with a “multiple-hit” model. In the classical “two-hit” hypothesis, insulin resistance is considered the first hit, followed by oxidative stress, lipid peroxidation, and mitochondrial dysfunction as subsequent hits.^[51] However, it is increasingly clear that additional, yet unidentified or poorly understood, factors also contribute to disease development.

Given their growing environmental prevalence and broad direct and indirect hepatotoxic effects, MNPs have been repeatedly hypothesized to play a role in MASLD pathogenesis.^[23,25] Evidence for this link comes predominantly from preclinical studies in rodents, fish, and avian models.

In a seminal mouse model of MASLD induced by a high-fat diet (HFD), intravenous administration of PS nanoparticles caused significant histopathological changes characterized by enhanced Kupffer cell infiltration and marked collagen fiber deposition—suggesting accelerated fibrosis compared with HFD alone.^[52] Similarly, Okamura et al.^[53] administered PS microplastics to C57BL/6J mice on either a normal diet (ND) or HFD for four weeks. Mice on HFD plus microplastics exhibited significantly elevated blood glucose, increased serum lipid levels, and higher MASLD activity scores compared with HFD-only controls. These effects were not seen in ND-fed mice, indicating that metabolic stress is necessary for microplastic-induced hepatic alterations.^[53]

Wang et al.^[54] reported that high doses of PS nanoparticles administered during gestation induced hepatic steatosis in adult female offspring, but not in males. These changes were associated with upregulated expression of genes involved in fatty acid uptake and triglyceride synthesis, indicating enhanced lipogenesis.^[54] Liu et al.^[55] demonstrated that mice receiving HFD plus MNPs in drinking water developed worse histopathological liver changes—such as inflammatory cell infiltration and ballooning degeneration—than HFD-only animals.

Wei et al.^[56] fed C57BL/6J mice an HFD containing 70 nm PS microspheres, which adsorbed proteins and agglomerated during transit in vivo. This promoted progression from HFD-induced hepatic steatosis to MASH via redox imbalance and mitochondrial calcium overload. Zhao et al.^[57] examined the gut–liver–adipose axis by administering PS beads (0.5 or 5 µm) at two concentrations (0.1 or 1 μg/mL) in drinking water. Mice exposed to smaller beads (0.5 µm) at higher concentration (1 μg/mL) developed elevated fasting plasma insulin, increased insulin resistance, obesity-associated microbiota changes, and adipose tissue gene expression patterns indicative of increased adipogenesis.

In aquatic models, zebrafish exposed to MNPs showed increased lipid accumulation, triglycerides, cholesterol, hepatic inflammation, and oxidative stress, along with a disrupted gut microbiota marked by a higher Firmicutes/Bacteroidetes ratio and elevated serum LPS.^[58] Boopathi et al.^[59] found that zebrafish exposed to both HFD and PE MNPs exhibited more severe hepatic necroinflammation resembling MASH than those fed HFD alone.

Chen et al.^[60] studied nanopolystyrene exposure in juvenile mandarin fish (Siniperca chuatsi) and found macrostructural and microstructural liver damage with oxidative stress after 21 days. In gilthead seabreams (Sparus aurata), dietary PS microplastics (1–20 μm) increased expression of genes involved in lipid synthesis and storage, upregulated pro-inflammatory cytokines in a dose-dependent manner, and induced histological changes including lipid accumulation, inflammation, and necrosis.^[61]

In avian models, Chen et al.^[62] reported that female Muscovy ducks co-exposed to cadmium (Cd) and PVC MNPs for two months showed hepatocyte morphological damage and impaired function.

Human data remain limited. Schwenger et al.^[63] conducted the first study examining MNPs in MASH, comparing fecal MNP levels in six lean healthy controls, six obese individuals with normal liver function, and eleven patients with MASH. While baseline fecal MNP levels did not differ significantly, MNP levels correlated positively with portal and total macrophages, as well as natural killer cells. Microplastic fibers were positively associated with Bifidobacteria abundance and negatively with Lachnospiraceae. In a 12-month follow-up after bariatric surgery, patients with persistent liver disease showed higher fecal MNP fragment levels than those whose histology normalized.^[63]

Micronanoplastics and Hepatic Cirrhosis

Given the strong preclinical evidence linking MNPs to MASLD pathogenesis, it is plausible that these contaminants may also contribute to progression toward cirrhosis. Notably, the incidence of MASLD-related cirrhosis has risen substantially in recent years.^[64]

Experimental studies support this hypothesis. PS nanoparticles have been shown to exacerbate liver fibrosis in mice with HFD-induced steatosis.^[52] Microplastics measuring 0.1 μm can directly enter hepatocytes from the circulation, where they activate nuclear factor-κB translocation and fibronectin expression^[65,66]—both processes implicated in fibrogenesis and cirrhosis development. Co-exposure to Cd and MNPs has been found to synergistically induce liver inflammation and fibrosis.^[38] Additionally, continuous inhalation of PS nanoplastics can promote liver fibrosis and trigger hepatocyte ferroptosis,^[67] a novel iron-dependent form of cell death associated with cirrhosis pathogenesis.^[68]

As previously noted, the only direct evidence of MNP accumulation in human liver tissue comes from cirrhotic samples.^[28] Moreover, a recent study using a functional 3D liver microtissue model—comprising primary human hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells—showed that long-term MNP exposure caused significant pathological alterations, including disruption of tissue architecture.^[42]

Micronanoplastics and Hepatocellular Carcinoma

Recent research has highlighted a potential mechanistic role for MNPs in hepatocarcinogenesis, particularly in the setting of chronic inflammation–driven malignant transformation.^[69] This pathway closely parallels the progression from MASLD to HCC, which can occur even in pre-cirrhotic stages.^[70]

In a comprehensive study using a multi-model approach, Kim et al.^[71] employed the Comparative Toxicogenomics Database to assess the human health implications of high-density PE microplastics. Their analysis identified an adverse outcome pathway involving aflatoxin B1– mediated HCC development. In another recent study, Huang et al.^[69] demonstrated that MNPs aggravated liver injury under infectious conditions and, through big data analysis, established a correlation between MNP pollution levels and human HCC. Importantly, they identified Spalt-like transcription factor 2 (SALL2)—an evolutionarily conserved molecule frequently dysregulated in various malignancies^[72]—as a potential oncogenic promoter in MNP-driven HCC. Liver transcriptome analysis further revealed activation of carcinogenesis pathways in MNP-exposed samples compared with pre-infection conditions.^[69]

Occupational medicine studies provide some of the most compelling clinical evidence linking specific MNPs to HCC. For example, exposure to PVC MNPs has been consistently associated with liver toxicity and an increased risk of both HCC and liver angiosarcoma, as reviewed by Zarus et al.^[73] A landmark epidemiological study reported 71 cases of primary liver cancer among 12,700 PVC and vinyl chloride workers, with a standardized mortality ratio of 2.40 (95% CI: 1.80–3.14).^[74] Other studies have similarly found a significant excess of primary liver tumors in PVC-exposed workers.^[75]

By contrast, the liver carcinogenic effects of occupational and environmental exposure to other MNP types in humans remain poorly understood.

Discussion

The Converging Crises: Plastic Pollution and Liver Diseases

The global burdens of advanced liver disease^[1,2,8] and plastic pollution^[29–31] are both increasing, raising the hypothesis that these two public health challenges may be interconnected,^[20–22] potentially through the mediating role of MASLD^[23,25]—a well-recognized and increasingly prevalent precursor to both cirrhosis and HCC.^[8,19,20] In recent years, there has been a surge in experimental studies demonstrating the hepatotoxic effects of MNPs in animal models.^[52–54,57] These studies consistently show that short-and medium-term MNP exposure leads to hepatic alterations closely resembling those seen in human MASLD and MASH. Furthermore, the potential direct and indirect hepatotoxic mechanisms of MNPs have been extensively examined using advanced analytical methods and summarized in several recent reviews.^[21–25]

MNPs as a “Second hit” in MASLD and Potential Sex-Related Effects

Our analysis of preclinical literature reveals two notable patterns. First, the evidence suggests that MNPs require pre-existing metabolic stress— typically induced in rodent models by an HFD^[52,53]—to trigger MASLD-like histological changes. Mice on a normal diet (ND) exposed to MNPs do not develop steatotic changes,^[52–54] supporting the hypothesis that MNPs may act as a “second hit” in the presence of metabolic derangement. Second, some studies have reported sex-specific effects, with female mice more susceptible to certain MNP-induced changes.^[54] This raises the possibility that sex hormones and/or sex-specific epigenetic mechanisms may influence the hepatic toxicological profile of MNPs.

Gaps in Current Research: The Need for Systematic Approaches and Quantification of MNPs in Human Blood

Despite the consistent findings from animal studies, research has not yet adopted a fully systematic approach to MNP characterization. Future studies should more rigorously compare primary versus secondary MNPs, assess different size fractions (microplastics, submicroplastics, nanoplastics), and investigate varied chemical compositions.

In humans, the role of MNPs in MASLD pathogenesis remains largely unexplored, with only a single pilot study offering preliminary insights.^[63] This is important because animal MASLD models do not perfectly replicate the human disease in clinical, biochemical, or histological terms.^[76]

Two methodological avenues could address this gap. First, following the approach of Horvatits et al.,^[28] MNPs could be detected and characterized in liver biopsy specimens from patients with MASLD/MASH. However, this technique is time-consuming and challenging to standardize across centers. An alternative is quantifying MNPs in human blood and analyzing their cross-sectional and longitudinal associations with MASLD presence, histological severity, and progression to cirrhosis or HCC.

Recent studies have demonstrated the feasibility of detecting MNPs in human blood. Using pyrolysis–gas chromatography/mass spectrometry (Py-GC-MS), PET, PE, PS, and PMMA were identified in healthy volunteers.^[77] Methodological refinements have since increased sensitivity, allowing detection of up to six high-production polymers, with PE most prevalent.^[78] Micro-Fourier transform infrared spectroscopy has also identified 24 polymer types in blood, present in 90% of participants.^[79] Although these advanced techniques are not yet practical for routine clinical use, the development of PS-specific antibodies^[80] raises the possibility of creating research-grade immunoassays for broader application.

MNPs as Potential Biomarkers in Advanced Fibrosis, Cirrhosis Progression, and Fibrosis Reversibility

Blood-based MNP measurements could have particular relevance in advanced liver disease, potentially serving as biomarkers of disease progression and prognosis. Cirrhosis can remain in a compensated state for years, with progression rates varying widely between individuals.^[81] This variability reflects the persistence of underlying injury and the presence of multiple pathogenic drivers.^[82] Investigating whether persistently high MNP levels or specific particle profiles predict decompensation risk is a promising research direction.^[83]

The role of MNPs in fibrosis regression also warrants attention. Although cirrhosis was once considered irreversible, evidence now shows that regression—demonstrated by reduced fibrosis scores—can occur under certain conditions.^[84] The triggers and thresholds determining reversibility remain unclear.^[85] Studying MNPs in this context may shed light on factors influencing both progression and potential reversal of cirrhosis.

MNPs and Hepatocellular Carcinoma: A New Frontier

Given the preclinical evidence that MNPs can worsen liver injury under infectious conditions^[69] and exacerbate metabolic stress–related damage,^[52–54] measuring blood MNP levels in high-risk populations—such as those with chronic viral hepatitis or MASLD—may help assess their relationship with future HCC incidence.

While current evidence linking MNPs to HCC in humans is limited, studies of MNP concentrations in relation to metastasis-free and overall survival could reveal novel prognostic markers. Existing biomarkers for HCC, such as α-fetoprotein, have significant limitations;^[86] additional markers could enhance risk stratification. Furthermore, if certain MNP types or patterns are associated with adverse outcomes, interventions targeting their accumulation or effects might be explored.

Incorporating MNP analysis into HCC research aligns with the broader trend toward precision hepatology.^[87,88] By integrating MNP data with other biomarkers and clinical parameters, clinicians could improve disease risk assessment, personalize treatment strategies, and enhance monitoring—ultimately advancing efforts against this aggressive malignancy. However, this remains a nascent research field, and substantial work is needed before MNPs can be considered reliable prognostic biomarkers.

Limitations

In this review, we provided a comprehensive overview of the literature on MNPs and their potential role in liver damage, with a particular focus on MASLD and advanced liver injury. A key strength of this narrative review is its broad search strategy, covering multiple databases—including PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar—and focusing on studies published in the past decade, representing the most recent and relevant period in the field.

However, most of the current evidence is derived from animal studies, with only a small proportion coming from human investigations. The available human studies have involved very limited sample sizes, which restricts the generalizability of their findings. Therefore, our interpretations should be considered with caution, and future large-scale clinical studies will be essential to confirm these observations.

Conclusion

Although substantial progress has been made in elucidating the hepatotoxic effects of MNPs in experimental models, their role in human MASLD and advanced liver conditions—including cirrhosis and HCC—remains largely unexplored. Bridging these knowledge gaps will require a multidisciplinary approach, integrating environmental science, epidemiology, toxicology, molecular biology, and hepatology.

Given the simultaneous global rise in plastic pollution and advanced liver diseases, advancing this line of research holds significant potential for improving public health outcomes.

Conflict of Interest

The authors have no conflict of interest to declare.

Financial Disclosure

The authors declared that this study has received no financial support.

Use of AI for Writing Assistance

The authors declared that they did not use any AI for writing assistance.

Author Contributions

Concept – YY, CS; Design – YY, CS; Supervision – YY; Fundings – YY; Materials – YY; Data Collection and/or Processing – CS, MU; Analysis and/or Interpretation – CS, MU, EK; Literature Search – CS, MU, EK; Writing – YY, CS, MU, EK; Critical Reviews – YY.

Peer-review

Externally peer-reviewed.