Letter to the Editor: Microplastics as promoters of metabolic dysfunction-associated steatotic liver disease: Mechanistic insights and implications

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and carries a substantial risk of progression to hepatocellular carcinoma. The detection of microplastics (MPs) in human tissues - including the brain, lung, liver, and blood - has emerged as an important environmental health concern. A recent study comprehensively summarized the potential mechanisms by which MPs may induce and exacerbate MASLD. The evidence discussed was largely derived from in vitro and preclinical studies and included hepatic lipid dysregulation, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory signaling, fibrogenesis, gut dysbiosis, and endocrine disruption. This article comments on the study by Rajak et al, published in the recent issue of the World Journal of Hepatology, and specifically highlights how MPs-induced autophagy dysfunction may contribute to MASLD progression and its potential clinical implications.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Non-alcoholic fatty liver disease; Steatosis; Autophagy; Lipophagy, Cytokines; Microplastics; Nanoplastics; Lysosome

Core Tip: Metabolic dysfunction-associated steatotic liver disease is the most prevalent chronic liver disease worldwide and carries a risk of progression to hepatocellular carcinoma. Microplastics have emerged as environmental hazards and have been detected in human tissues, including the liver, brain, and blood. Recent preclinical evidence links microplastic exposure to metabolic dysfunction-associated steatotic liver disease through mechanisms involving metabolic stress, inflammation, and autophagy dysfunction, with potential clinical implications.

TO THE EDITOR

Metabolic dysfunction-associated steatotic liver disease (MASLD), also known as metabolic dysfunction-associated fatty liver disease and formerly non-alcoholic fatty liver disease, represents the most prevalent chronic liver disease worldwide. The clinicopathology of MASLD encompasses a broad spectrum, ranging from simple steatosis to non-alcoholic steatohepatitis, with a risk of progression to advanced fibrosis, cirrhosis, and hepatocellular carcinoma[1]. Diagnosis is via radiological evidence of hepatic steatosis in combination with one or more metabolic risk factors, including overweight or obesity, type 2 diabetes mellitus, and metabolic dysregulation[2]. In children, MASLD can be attributed to genetic predisposition, nutrition, and environmental exposure[3].

MICROPLASTICS-INDUCED AUTOPHAGY DYSFUNCTION IN MASLD

Mechanistically, MASLD is initiated by insulin resistance, which leads to hepatic steatosis, oxidative stress, lipotoxicity, and inflammation driven by mitochondrial dysfunction, lysosomal impairment, endoplasmic reticulum stress, DNA damage, and the release of pro-inflammatory cytokines. These events promote the activation of Kupffer cells and hepatic stellate cells, ultimately resulting in non-alcoholic steatohepatitis, fibrosis, and disease progression. Importantly, impaired autophagy has been listed as playing a central role in the pathogenesis and progression of MASLD[1].

Autophagy (macroautophagy, also termed bulk autophagy) is a lysosomal degradation pathway responsible for the clearance and recycling of nearly all cellular components, including damaged organelles, misfolded or aggregated proteins, and excess lipid droplets, particularly under stress conditions such as oxidative or metabolic stress. Autophagy may also proceed selectively, targeting specific substrates such as mitochondria (mitophagy) or lipid droplets (lipophagy). The early stage of autophagy is characterized by the formation of Beclin-1-mediated autophagosomal membranes, which sequester cellular components into double-membrane vesicles termed autophagosomes, a process mediated by LC3, a key autophagy marker. Autophagosomes subsequently fuse with lysosomes via the lysosomal membrane protein 2 to form autolysosomes, where the cargo is degraded by lysosomal cathepsins (late stage). Importantly, autophagy is a dynamic process and is best assessed by measuring autophagic flux, defined as the rate of autophagic degradation[1,4].

In this context, Rajak et al[5] recently presented, in World Journal of Hepatology, a concise overview of emerging evidence on the effects of microplastics (MPs) on hepatic metabolism, including mitochondrial homeostasis and endocrine regulation, with potential implications for the progression of MASLD. This article comments on and expands upon the key points raised in that study. The databases consulted for this article included PubMed, Google Scholar, the Directory of Open Access Journals, and ScienceDirect. The content is based on a curated selection of relevant literature published over the past 10 years, highlighting current trends and key findings in the field.

The study by Rajak et al[5] links current evidence regarding exposure to MPs to key pathways involved in the pathogenic progression of MASLD, including hepatic lipid dysregulation, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory signaling, fibrogenesis, gut dysbiosis, and endocrine disruption. These mechanisms are well-aligned with established drivers of MASLD and metabolic inflammation[1,4,6,7]. The authors further include recent preclinical studies and a schematic diagram depicting direct hepatic and extra-hepatic effects, enhancing the clarity and educational value of the article.

However, the study by Rajak et al[5] has several limitations that require further attention. First, the literature search and study selection strategy were not described, which limits the transparency and reproducibility of the minireview. Clear reporting of the search databases, keywords, inclusion and exclusion criteria, and study selection process is essential to enable readers to assess the robustness and reliability of the findings.

Next, mechanistic evidence, including dose, particle size, and routes of exposure, from in vitro and animal models may not accurately translate into relevant human exposure scenarios[8,9]. Despite the acknowledgement of this limitation in the conclusion, a critical appraisal that is consistent throughout the paper would improve interpretative balance and reduce the chances of over-extrapolation.

The authors also frequently discuss MPs and nanoplastics (NPs) as one group, whereas differences in particle size, polymer composition, surface charge and chemical additives between MPs and NPs critically affect biodistribution and toxicity, as reported widely in literature. Distinguishing the two particles and polymer types would offer a more precise understanding of their mechanisms and improve translational relevance. MPs are artificial polymer particles with sizes ≤ 5 mm and are not necessarily the end products of plastic degradation, as they can further fragment into NPs. NPs are defined as particles with sizes ranging from 1 nm to 1 μm[10,11]. Compared with MPs, NPs have been shown to induce lysosomal dysfunction in vitro, ultimately leading to impaired autophagic flux[12]. Accordingly, the toxicity of MPs/NPs is closely related to particle size, with smaller particles generally exhibiting greater bioactivity and cytotoxicity due to more efficient cellular internalization[13]. However, the available evidence is predominantly derived from in vitro and animal studies. Although these models provide important mechanistic insights, the translation of such findings to human exposure scenarios remains uncertain, particularly given differences in particle size, dose, and routes of exposure, which warrant further investigation.

Although the authors address mitochondrial dysfunction and mitophagy, the study lacks a critical discussion of the broader role of bulk autophagy and selective autophagy i.e. lipophagy, and their communication with endoplasmic reticulum and oxidative stress, as well as inflammation. Autophagy has been established as a central regulator of hepatic lipid homeostasis and MASLD progression in literature[1,4,14,15]. Furthermore, there is evidence that autophagy and autophagic flux can be impaired due to exposure to a combination of MPs and metabolic stressors, exacerbating hepatic steatosis and fibrosis[16]. In addition, NPs have been reported to induce lysosomal damage, thereby preventing autolysosome formation and blocking lipophagic flux in hepatocytes, which exacerbates hepatic steatosis[17]. Figure 1 illustrates the mechanisms by which MPs/NPs initiate or promote MASLD by damaging lysosomes and suppressing the late stages of autophagy, including lipophagy and autophagic flux[12,17].

Figure 1 Microplastics and nanoplastics may induce and exacerbate metabolic dysfunction-associated steatotic liver disease by causing lysosomal dysfunction, thereby impairing the late stages of bulk and selective autophagy, such as lipophagy, and blocking autophagic flux. MPs: Microplastics; NPs: Nanoplastics; MASLD: Metabolic dysfunction-associated steatotic liver disease.

In humans, autophagic flux can be estimated by measuring the autophagosomal marker LC3-II in peripheral blood mononuclear cells isolated from blood samples treated with lysosomal inhibitors, such as chloroquine. An increase in LC3-II levels accompanied by a reduction in its substrate p62 indicates enhanced autophagic flux[1,4]. In patients with MASLD, monitoring these markers may have important diagnostic and therapeutic relevance; however, additional studies are required to clarify their relationship with circulating MP/NP levels in humans. Moreover, current limitations - including interindividual variability, lack of assay standardization, and uncertain correlation with hepatic autophagy - should be acknowledged to provide balance and credibility.

Finally, the translational relevance of this field remains limited by the paucity of clinical data. Although MPs have been detected in human cirrhotic liver tissue[18] and in decedent human brain samples[19], large-scale epidemiological and longitudinal human studies linking microplastic exposure to the severity and progression of MASLD are still lacking. Future research should prioritize in-depth evaluation of microplastic exposure biomarkers, their interactions with established metabolic risk factors, and their potential implications for clinical risk stratification and public health policy. Well-designed clinical studies are needed to correlate microplastic exposure - such as circulating MP/NP levels - with autophagy markers and MASLD severity and disease progression.

CONCLUSION

In conclusion, this study provides an up-to-date and valuable synthesis of the potential role of MPs as environmental modifiers in the progression of MASLD. Nevertheless, greater methodological transparency, more consistent critical appraisal, and the inclusion of discussion on autophagy and translational relevance would further strengthen its scientific impact. Moreover, assessment of autophagy-related markers in blood samples from patients with MASLD, including pediatric populations, and their relationship with circulating MPs/NPs may offer diagnostic and therapeutic relevance and warrants further investigation, positioning autophagy assessment as a testable clinical bridge between environmental exposure and MASLD progression.