What is the clinical evidence from this study?

Study design: Other. Population: Metabolic dysfunction-associated steatohepatitis (MASH). Intervention: Compound 3d vs. Model (HFD-fed mice). Primary outcome: Serum biochemical parameters (TG, TC, LDL-C, TNF-α) and liver histopathology (p=<0.05).

April 29, 2025Open Access

Compound 3d Attenuates Metabolic Dysfunction-Associated Steatohepatitis via Peroxisome Proliferator-Activated Receptor Pathway Activation and Inhibition of Inflammatory and Apoptotic Signaling

Q: What are the key findings of this study?

In a high-fat diet-induced MASH mouse model, compound 3d (30 mg/kg) significantly lowered serum triglycerides (39%), total cholesterol (32%), LDL-C (45%), and TNF-α (57%) (p<0.05 vs. model).

SZShouqing ZhangTianjin University of Science and Technology JYJiajia YuTianjin University of Science and Technology SBSule BaiTianjin University of Science and Technology

Key Result

In a high-fat diet-induced MASH mouse model, compound 3d (30 mg/kg) significantly lowered serum triglycerides (39%), total cholesterol (32%), LDL-C (45%), and TNF-α (57%) (p<0.05 vs. model).

Structured PICO

Does compound 3d attenuate metabolic dysfunction-associated steatohepatitis in preclinical models?

Population

In vitro cell lines (L02 hepatocytes, RAW264.7 macrophages) and an in vivo high-fat diet-induced MASH model in C57BL/6 mice.

Intervention

Compound 3d (novel elafibranor derivative), 30 mg/kg in vivo

Comparator

Untreated model (HFD-fed mice without treatment) and untreated cells

Outcome

Lipid accumulation, inflammatory responses, serum biochemical parameters (TG, TC, LDL-C, ALT, AST, TNF-α, NO, IL-6), liver histopathology, and proteomic profilingsurrogate

Compound 3d, a novel elafibranor derivative, demonstrates therapeutic potential for MASH in preclinical models by improving lipid metabolism, reducing inflammation, and modulating gut microbiota.

Main Result

p-value: p=<0.05

Abstract

Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) lacks effective therapies. This study aimed to evaluate the therapeutic potential of compound 3d, a novel elafibranor derivative, focusing on its dual mechanisms of PPAR pathway activation and p38 MAPK signaling inhibition. Methods: Integrated in vitro and in vivo approaches were employed. In vitro, free fatty acid (FFA)-induced lipid accumulation in L02 hepatocytes and lipopolysaccharides (LPSs)-stimulated inflammatory responses in RAW264.7 macrophages were used to evaluate lipid metabolism and anti-inflammatory effects. In vivo, a high-fat diet (HFD)-induced MASH model in C57BL/6 mice assessed serum biochemical parameters (triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor-α (TNF-α), nitric oxide (NO), and interleukin-6 (IL-6)), liver histopathology (H p < 0.001) and p38 MAPK pathway inhibition (54% reduction in p-p38, 61% decrease in caspase-8; 1.8-fold increase in Bcl-2; p < 0.01). Gut microbiota analysis revealed enrichment of beneficial taxa (Lactobacillus: 2.7-fold increase; Bifidobacterium: 1.9-fold rise) and reduced pathogenic Proteobacteria (68% decrease, p < 0.05). Conclusions: Compound 3d alleviates MASH via PPAR-mediated lipid metabolism enhancement and p38 MAPK-driven inflammation/apoptosis suppression, with additional gut microbiota modulation. These findings highlight 3d as a multi-target therapeutic candidate for MASH.

问 AI

Bookmark

View Full Paper