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Background <p>Liver fibrosis is a progressive disease characterized by excessive extracellular matrix deposition and metabolic dysregulation, and exposure to environmental toxins such as bisphenol A (BPA). Clinical management of liver fibrosis is cumbersome because of limited therapeutic options. Niclosamide (NIC) is an antihelmintic drug repurposed for the treatment of liver fibrosis. However, the treatment of liver fibrosis with NIC is affected by its poor solubility, bioavailability, and targetability. To address these issues, a niclosamide loaded hyaluronic acid and mannose grafted multifunctional liposomal formulation (NIC-HA-MN-Lipo) was developed.</p> Methods <p>NIC-HA-MN-Lipo was prepared by thin-film hydration method and systematically characterized. The present study focused on high-field 800&#xa0;MHz <sup>1</sup>H NMR-based serum metabolomics to elucidate metabolic alterations in BPA induced hepatic fibrosis and assess the restorative effect of NIC-HA-MN-Lipo in a rat model.</p> Results <p>The formulation exhibited vesicular size, polydispersity index, and zeta potential values within the acceptable range, with high encapsulation efficiency. Surface morphology examined by transmission electron microscopy (TEM) confirmed spherical vesicles with smooth surfaces, supporting the stability and suitability of the formulation for therapeutic application. Cellular uptake studies revealed that LX-2 cells internalized COU-HA-MN-Lipo more efficiently than COU-Lipo. Haemocompatibility studies showed modest haemolysis, indicating its biocompatibility and safely with blood cells. Multivariate statistical analyses, including PCA, and PLS-DA identified significant disruptions in crucial metabolic pathways following BPA exposure, such as glycolysis or gluconeogenesis, TCA cycle, pyruvate metabolism, and amino acid pathways. Treatment with NIC-HA-MN-Lipo successfully rectified these disruptions, particularly reinstating glycerolipid metabolism, pyruvate metabolism, and various amino acid metabolic pathways. Distinct group separations in multivariate models further confirmed the systemic metabolic reprogramming by BPA and the therapeutic impact of NIC-HA-MN-Lipo.</p> Conclusion <p>NIC-HA-MN-Lipo showed superior potential against hepatic fibrosis cells with good haemocompatibility. The metabolomics-based approach highlights key metabolic pathways associated with BPA-induced hepatic fibrosis and illustrates the protective efficacy of NIC-HA-MN-Lipo in recovering metabolic homeostasis. These findings provide mechanistic insights into BPA-induced liver fibrosis and establish metabolomics as a powerful tool for biomarker discovery and evaluation of anti-fibrotic interventions.</p> Graphical Abstract <p></p>

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Metabolic dysregulation in bisphenol A-induced hepatic fibrosis and its therapeutic reversal by niclosamide-loaded multifunctional liposomes: an NMR-based serum metabolomics

  • 期刊论文

  • 发表日期：

    2026年5月7日

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  • Vipin Kumar,
  • Gurvinder Singh,
  • Amita Singh,
  • Anurag Kumar Gautam,
  • Km Prachi,
  • Dinesh Kumar,
  • Vijayakumar Mahalingam Rajamanickam

摘要

Background

Liver fibrosis is a progressive disease characterized by excessive extracellular matrix deposition and metabolic dysregulation, and exposure to environmental toxins such as bisphenol A (BPA). Clinical management of liver fibrosis is cumbersome because of limited therapeutic options. Niclosamide (NIC) is an antihelmintic drug repurposed for the treatment of liver fibrosis. However, the treatment of liver fibrosis with NIC is affected by its poor solubility, bioavailability, and targetability. To address these issues, a niclosamide loaded hyaluronic acid and mannose grafted multifunctional liposomal formulation (NIC-HA-MN-Lipo) was developed.

Methods

NIC-HA-MN-Lipo was prepared by thin-film hydration method and systematically characterized. The present study focused on high-field 800 MHz 1H NMR-based serum metabolomics to elucidate metabolic alterations in BPA induced hepatic fibrosis and assess the restorative effect of NIC-HA-MN-Lipo in a rat model.

Results

The formulation exhibited vesicular size, polydispersity index, and zeta potential values within the acceptable range, with high encapsulation efficiency. Surface morphology examined by transmission electron microscopy (TEM) confirmed spherical vesicles with smooth surfaces, supporting the stability and suitability of the formulation for therapeutic application. Cellular uptake studies revealed that LX-2 cells internalized COU-HA-MN-Lipo more efficiently than COU-Lipo. Haemocompatibility studies showed modest haemolysis, indicating its biocompatibility and safely with blood cells. Multivariate statistical analyses, including PCA, and PLS-DA identified significant disruptions in crucial metabolic pathways following BPA exposure, such as glycolysis or gluconeogenesis, TCA cycle, pyruvate metabolism, and amino acid pathways. Treatment with NIC-HA-MN-Lipo successfully rectified these disruptions, particularly reinstating glycerolipid metabolism, pyruvate metabolism, and various amino acid metabolic pathways. Distinct group separations in multivariate models further confirmed the systemic metabolic reprogramming by BPA and the therapeutic impact of NIC-HA-MN-Lipo.

Conclusion

NIC-HA-MN-Lipo showed superior potential against hepatic fibrosis cells with good haemocompatibility. The metabolomics-based approach highlights key metabolic pathways associated with BPA-induced hepatic fibrosis and illustrates the protective efficacy of NIC-HA-MN-Lipo in recovering metabolic homeostasis. These findings provide mechanistic insights into BPA-induced liver fibrosis and establish metabolomics as a powerful tool for biomarker discovery and evaluation of anti-fibrotic interventions.

Graphical Abstract