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. 2025 May 30:20:6949-6962.
doi: 10.2147/IJN.S515107. eCollection 2025.

Carrier-Free Silibinin/Sorafenib Microparticles Alleviate Metabolic Dysfunction-Associated Steatotic Liver Disease by Modulating Fatty Acid Metabolism

Feifei Han #  1 , Haiping Wang #  1   2 , Li Wang  1 , Limei Fan  1 , Sibei Peng  1 , Xiaoying Hou  1   2 , Xiji Shu  1   2 , Binlian Sun  1   2 , Yuchen Liu  1   2
Affiliations

Carrier-Free Silibinin/Sorafenib Microparticles Alleviate Metabolic Dysfunction-Associated Steatotic Liver Disease by Modulating Fatty Acid Metabolism

Feifei Han et al. Int J Nanomedicine. .

Abstract

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive fat accumulation in the liver, is the most prevalent cause of chronic liver disease globally. The clinical use of pharmacological agents such as silibinin and sorafenib is limited due to poor water solubility, low bioavailability, and potential side effects, necessitating innovative therapeutic approaches.

Methods: In this study, we developed self-assembled, carrier-free microparticles of silibinin and sorafenib (SIL-SOR-MPs) using magnetic stirring and evaluated their therapeutic effects on MASLD both in vitro and in vivo.

Results: Compared to free SIL and free SOR, SIL-SOR-MPs significantly reduced lipid accumulation in HepG2 cells and effectively alleviated hepatic steatosis and liver damage in mice. Mechanistic investigations further showed that SIL-SOR-MPs more effectively down-regulated lipid synthesis genes and up-regulated genes involved in lipid oxidation.

Discussion: In summary, our study highlights that carrier-free SIL-SOR-MPs demonstrate the ability to reverse the progression of MASLD and present a promising therapeutic strategy.

Keywords: fatty acid metabolism; metabolic dysfunction-associated steatotic liver disease; self-assembled carrier-free microparticles; silibinin; sorafenib.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Scheme 1
Scheme 1
Schematic illustration of preparation of self-assembled, carrier-free silibinin/sorafenib microparticles and the treatment mechanism on MASLD.
Figure 1
Figure 1
Preparation and characterization of SIL-SOR-MPs. (A) Schematic illustration of the synthesis process of SIL-SOR-MPs. (B) TEM image showing the morphology of SIL-SOR-MPs. (C) Particle size distribution of SIL-SOR-MPs as measured by dynamic light scattering. (D) Zeta potentials values of SIL-SOR-MPs, indicating the surface charge. (E) UV/Vis spectra of SIL, SOR and SIL-SOR-MPs in double distilled H2O or DMSO, showing the characteristic absorption peaks. (F) UV/Vis spectra of SIL-SOR-MPs in varying concentrations of NaCl, illustrating the effect of electrostatic interactions on the particle absorption. (G) UV/Vis spectra comparing 2% SDS, SIL-SOR-MPs alone, SIL-SOR-MPs with 2% SDS, highlighting changes in spectral behavior upon interaction with SDS.
Figure 2
Figure 2
Cytotoxicity and lipid-lowering effects of SIL-SOR-MPs on HepG2 cells in vitro. (A) Cytotoxicity assessment of SIL-SOR-MPs in HepG2 cells. (B) Quantitative analysis of TC contents in cells. (C) Quantitative analysis of TG levels in cells. (D) Oil red O and Nile Red staining showing lipid accumulation in different treatment groups. (E) Quantitative analysis of fatty acid synthesis gene expression (SREBP-1c, FAS, ACC1). (F) Quantitative analysis of fatty acid oxidation gene expression (PPAR-α, PPAR-γ, CPT1α). *P < 0.05, **P < 0.001, ***P < 0.0001 (FFA vs others). Scale bar: 20 μm.
Figure 3
Figure 3
The distribution of SIL-SOR-MPs in the liver. Quantitative analysis was conducted to assess the distribution of SIL (A) and SOR (B) in mice following intraperitoneal injection. Drug content was measured in both the free SIL/SOR and SIL-SOR-MPs groups at 2, 6, 12, 24, and 48 hours post-administration. Each group consisted of 3 mice (n=3). *p < 0.05, ***p < 0.0001 (Free SIL/SOR vs SIL-SOR-MPs).
Figure 4
Figure 4
SIL-SOR-MPs inhibit HFD-induced MASLD progression. (A) Schematic representation of the animal experiment design. The drug treatments of the animals were divided into 6 groups: ND, HFD, HFD+SIL, HFD+SOR, HFD+Free SIL/SOR and HFD+SIL-SOR-MPs. (B) Photographs of MASLD mice following different treatment interventions. (C) Changes in body weight of mice throughout the treatment period. (D) Measurement of liver weight at the end point of experiments. (E) After 6 weeks of treatment, liver morphology (top panel), H&E staining (middle panel), and Oil red O staining (bottom panel) were analyzed for each group of mice. *p < 0.05, **p < 0.001, ***p < 0.0001 (HFD vs others). ND: normal-diet, HFD: high-fat diet. Scale bar: 20 μm, 400× magnification.
Figure 5
Figure 5
Regulatory effects of SIL-SOR-MPs on lipid metabolism. (A) TC levels in liver tissue across experimental groups. (B) TG levels in liver tissue across experimental groups. (C–F) Serum levels of TC, TG, ALT and AST in each experimental group. (G) Quantitative analysis of genes expression related to lipid synthesis and oxidation (SREBP-1c, FAS, ACC1, PPAR-α, ACOX1, CPT1α). *p < 0.05, **p < 0.001, ***p < 0.0001 (HFD vs others).
Figure 6
Figure 6
In vivo safety analysis. After 6 weeks of drug treatment, histological analysis of the heart, spleen, lung, and kidney were performed using H&E staining to assess potential toxicity. Scale bar: 20 μm.
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