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Polystyrene Microplastics Exacerbate Mitochondrial Damage by Inhibiting PTK6-Dependent Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease

ABSTRACT: The toxic mechanisms of microplastics (MPs), which are emerging environmental pollutants, remain uncertain. MPs have been linked to severe liver metabolic disorders; however, the underlying mechanisms remain unclear. In this study, we found that the plasma concentrations of MPs, especially polystyrene MPs (PS-MPs), were higher in patients with metabolic dysfunction–associated steatotic liver disease (MASLD) than in healthy controls and showed a positive correlation with liver enzymes and serum lipids, as detected by pyrolysis gas chromatography–mass spectrometry. Exposure to PS-MPs of 2 μm in size resulted in a significant increase in the severity of fibrosis and inflammation and exacerbated mitochondrial dysfunction and mitophagy disorders in livers of db/db mice and palmitic acid (PA)–treated HepG2 cells. RNA sequencing and proteomics analyses demonstrated that the mitophagy and the autophagy-related protein tyrosine kinase 6 (PTK6) underwent significant changes. Molecular docking, surface plasmon resonance (SPR), and molecular dynamics studies confirmed that PS-MPs stably interacted with PTK6. Furthermore, when PTK6 was silenced, PS-MPs treatment failed to exacerbate mitophagy in PA-treated HepG2 cells and PS-MPs inhibited mitophagy in mitophagy agonist CCCP-stimulated HepG2 cells. Collectively, these findings suggest that PS-MPs exacerbate liver damage and mitochondrial damage via PTK6-mediated mitophagy in MASLD, providing valuable insights into the hepatotoxic effects of MPs on human liver health and suggesting potential therapeutic targets for MASLD

ORGANISM(S): Homo Sapiens

SUBMITTER: Xueqi Liu

PROVIDER: PXD075729 | iProX | Mon Mar 16 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:<p>Type 2 diabetes mellitus (T2DM) with metabolic syndrome-associated steatohepatitis (MASLD) is a complex metabolic comorbidity characterized by hyperglycemia, pancreatic β-cell dysfunction, and hepatic lipid metabolism disorders, in which gut microbiota dysbiosis and abnormal PPARγ signaling play pivotal roles. Zhaqu Compound (ZQC), a traditional Chinese herbal formula, has demonstrated clinical efficacy in improving glucose and lipid metabolism, though its mechanisms remain unclear. In this study, db/db mice with T2DM-MASLD were treated for 12 weeks with ZQC, metformin, or saline, and metabolic outcomes were evaluated via blood glucose, lipid profiles, hepatic lipid accumulation, hepatocyte ultrastructure, gut microbiota (16S rRNA), non-targeted metabolomics, and liver transcriptomics. In high-glucose + palmitate-induced HepG2 cells, ZQC-containing serum and the PPARγ agonist GW1929 were applied, and Western blot was used to assess key gluconeogenic and lipogenic proteins. LC-MS, network pharmacology, and molecular docking identified major ZQC components and their potential interactions with PPARγ. ZQC improved glycemia, insulin resistance, and lipid profiles, and alleviated hepatic steatosis. It increased beneficial gut bacteria (Bacteroidetes, Lactobacillales) and partially restored Lachnospiraceae and Muribaculaceae, modulated amino acid metabolism and AGE-RAGE/mTOR pathways, and activated hepatic PPARγ signaling while regulating fatty acid and arachidonic acid metabolism. In HepG2 cells, ZQC reduced lipid droplet accumulation, lowered triglyceride and total cholesterol levels, enhanced glucose uptake, downregulated key gluconeogenic and lipogenic proteins, and moderately decreased PPARγ and its downstream transporters (CD36, FABP4). N-phenethylhexadecanamide, palmitic acid, and isoflavone likely mediate these effects. Collectively, ZQC improves glucose and lipid metabolism in T2DM with MASLD by modulating gut microbiota, moderately regulating PPARγ signaling, and enhancing β-cell function, providing mechanistic insight into its therapeutic potential.</p>

Project description:Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic insulin resistance (IR) and impaired lipid–glucose metabolism. Sodium butyrate (NaB), a short-chain fatty acid (SCFA), may improve metabolic homeostasis, but its actions in MASLD-related IR remain unclear. This study investigated the therapeutic effects and mechanisms of NaB in palmitate (PA)-induced insulin-resistant hepatocytes and high-fat diet (HFD)-induced MASLD mice. Methods: PA-treated HepG2 cells received NaB (0.5–1.5 mM). Lipid accumulation, glucose uptake, glycogen content, and metabolic gene and protein expression were analyzed using biochemical assays, staining, qPCR, Western blotting, and RNA-seq. In vivo, C57BL/6 mice were fed an HFD for 16 weeks and then treated orally with NaB (200 or 400 mg/kg/day) for 8 weeks. Metabolic phenotypes, liver histology, and major signaling pathways were analyzed. Results: In PA-induced HepG2 cells, NaB dose-dependently decreased triglyceride, total cholesterol, low-density lipoprotein cholesterol, and non-esterified fatty acid levels, while increasing high-density lipoprotein cholesterol, glucose uptake, and glycogen storage. NaB suppressed lipogenesis (↓SREBP1c, ↓FASN), enhanced fatty acid oxidation (↑PGC-1α, ↑PPARα, ↑CPT1A), restored GPR43–CaMKK2–adenosine monophosphate-activated protein kinase (AMPK)α–SIRT1 signaling, and activated PI3K/AKT signaling (↑p-IRS1, ↑p-PI3K, ↑p-AKT, ↑GLUT2), thereby reducing gluconeogenic markers (↓FOXO1, ↓PCK1, ↓G6PC1) and increasing glycogen synthase (↑GS). Transcriptomics confirmed enrichment of PPARα and metabolic pathways. In HFD-fed mice, NaB reduced body weight, improved lipid profiles, alleviated steatosis, improved glucose tolerance and insulin sensitivity, and restored liver glycogen, with greater effects at the higher dose. Conclusion: NaB alleviates hepatic steatosis and IR in MASLD by activating AMPK and PI3K/AKT pathways, promoting fatty acid oxidation, and enhancing glycogen synthesis. NaB may serve as a promising multi-target metabolic modulator for MASLD.

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Polystyrene Microplastics Exacerbate Mitochondrial Damage by Inhibiting PTK6-Dependent Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease

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