Zinc oxide nanoparticles disrupt peroxisome-endoplasmic reticulum contacts and increase very-long-chain fatty acid content.

Summary

In vivo and in vitro models show that ZnO nanoparticles elevate hepatic VLCFAs and disrupt peroxisomal β-oxidation and Po-ER contacts by downregulating ACBD5 through the SIRT1–FOXO3 axis. These mechanistic data raise safety considerations for ZnO-containing topical products that could alter systemic lipid homeostasis upon exposure.

Key Findings

• ZnO nanoparticles increased hepatic VLCFAs, triglycerides, and total cholesterol after 10 weeks in vivo.
• Peroxisomal β-oxidation and peroxisome–ER contacts were reduced in vivo and in hepatocyte cultures.
• ZnO nanoparticles downregulated ACBD5; overexpression rescued and knockdown mimicked the phenotype.
• FOXO3 directly regulates ACBD5; ZnO nanoparticles increased acetylation, inhibited FOXO3 nuclear entry, and reduced SIRT1, implicating SIRT1-mediated FOXO3 deacetylation (K243).

Clinical Implications

Safety dossiers for ZnO-based sunscreens should consider biomarkers of peroxisomal function (e.g., ACBD5) and systemic lipid endpoints; formulations minimizing systemic exposure and post-market surveillance for lipid disturbances may be warranted.

Limitations

• Primary animal model is fish; human relevance and dermal exposure scenarios were not directly tested.
• Single dietary dose (10 mg/kg) and 10-week duration limit dose–response and long-term risk characterization.

Future Directions

Validate the SIRT1–FOXO3–ACBD5 signature in mammalian skin and systemic tissues under dermal ZnO exposure, and incorporate these biomarkers into cosmetic safety assessments.