Acetylshikonin mitigates diet-induced MASLD by targeting PPARγ-mediated metabolic dysfunction

Area of Science:

• Hepatology
• Pharmacology
• Natural Products Research

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern with no specific treatments.
• Dietary factors significantly contribute to MASLD pathogenesis, highlighting the need for novel therapeutic strategies.
• Natural bioactive compounds represent a promising avenue for MASLD intervention.

Purpose of the Study:

• To identify and evaluate acetylshikonin (AS), a traditional Chinese medicine component, as a potential therapeutic agent for MASLD.
• To elucidate the underlying molecular mechanisms by which AS exerts its effects on MASLD.
• To investigate the efficacy of AS in both in vivo and in vitro models of MASLD.

Main Methods:

• MASLD was induced in male mice using high-fat/high-cholesterol diets or CCl4, followed by AS treatment.
• In vitro studies utilized hepatocytes treated with fatty acids (PA/OA).
• Integrated network pharmacology, molecular docking, thermal shift assays, and Western blotting were employed to explore mechanisms.

Main Results:

• AS treatment significantly reduced hepatic steatosis and liver fibrosis in vivo.
• In vitro, AS suppressed lipid accumulation and inflammatory responses in hepatocytes.
• AS downregulated key genes in lipid metabolism, inflammation, and fibrosis pathways, primarily by targeting PPARγ.

Conclusions:

• Acetylshikonin demonstrates significant therapeutic potential for diet-induced MASLD.
• AS acts by targeting the PPARγ signaling pathway, reducing lipid deposition, inflammation, and fibrosis.
• These findings support the development of AS as a natural product-based therapy for MASLD and related liver diseases.