3β-trans-CLD alleviates metabolic dysfunction-associated steatotic liver disease (MASLD) via modulating the IDO1/Nrf2/SREBP1/SCD1 axis in vitro.

Authors

Yuying Hu, Yiren Yang, Jie Liu, Huiyuan Gao, Xiaowen Jiang, Yue Jin

Published in

Fitoterapia. Pages 107567. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Approved pharmacotherapies for metabolic dysfunction-associated steatotic liver disease (MASLD) remain limited, and targeted therapies with high efficacy and favorable safety profiles are urgently needed. Leptopus lolonum is rich in triterpenoids and has hepatoprotective activity; however, its systematic studies are lacking. The aim of this study was to systematically evaluate the therapeutic potential and underlying mechanisms of triterpenoids, especially compound 3β-trans-CLD, in MASLD. To evaluate the efficacy of 3β-trans-CLD, free fatty acid (FFA)-induced HepG2 and L02 hepatocyte models were established. Lipid accumulation, oxidative stress, and inflammatory responses were assessed, and transcriptomic profiling was conducted. Rescue experiments were performed using IDO1 and Nrf2 inhibitors to dissect the underlying mechanism. Treatment with 3β-trans-CLD restored mitochondrial membrane potential (JC-1 staining), diminished superoxide anion levels (DHE staining), and attenuated lipid accumulation, as reflected by decreased Oil Red O staining and lower TG and TC contents. Correspondingly, 3β-trans-CLD downregulated key lipogenic regulators FXR, SREBP1, and FASN and concurrently activated the Nrf2-Keap1-HO-1 antioxidant axis. Furthermore, 3β-trans-CLD significantly suppressed the expression of pro-inflammatory cytokines (TNF-α and IL-1β) and inhibited NF-κB and IκBα phosphorylation in FFA-induced HepG2 and L02 cells. Transcriptomic profiling identified a marked reduction in IDO1, PCSK9, and SCD expression, all of which displayed strong negative correlations with hepatocellular TG and TC levels. Mechanistically, these results demonstrated that 3β-trans-CLD counteracted MASLD-driven pathological alterations through coordinated regulation of the IDO1/Nrf2/SREBP1/SCD1 signaling cascade. These findings suggest that 3β-trans-CLD counteracts MASLD-driven pathological changes by coordinately regulating the IDO1/Nrf2/SREBP1/SCD1 signaling cascade in vitro.

PMID:
43008948
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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