Senkyunolide A mitigates lipid deposition in hyperlipidemic hepatocytes through SIRT6-mediated suppression of oxidative stress and fetuin-A

Senkyunolide A (SenA), a phthalide compound isolated from celery seed essential oil, is known for its antiinflammatory and antioxidant properties in various disease models. However, its impact on hepatic lipid metabolism and associated molecular mechanisms remain unclear. This study investigated the protective effects of SenA against lipotoxicity-induced hepatic steatosis and explored its underlying pathways. Lipid accumulation was assessed via Oil Red O staining, whereas protein expression was analyzed via Western blotting. Apoptosis was evaluated through TUNEL staining, caspase-3 activity, and cell viability assays. Oxidative stress was measured via DCFDA-based ROS detection and assays for MDA and H2O2. The role of SIRT6 was examined through siRNA-mediated knockdown. SenA treatment significantly reduced lipid deposition, apoptosis, oxidative stress, and fetuin-A expression in palmitate-treated hepatocytes. It also increased the expression of SIRT6 and Nrf2, two key regulators of metabolic and redox homeostasis. Silencing SIRT6 diminished these protective effects, indicating its essential role in mediating SenA activity. These findings suggest that SenA mitigates hepatic steatosis by modulating oxidative stress and metabolic dysfunction via SIRT6/Nrf2 signaling. As a natural bioactive compound, SenA offers promise for the development of safer therapeutic strategies for managing nonalcoholic fatty liver disease (NAFLD), which has broader relevance to metabolic health.

Journal

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Year

2025

Volume

771

ISSN

0006-291X

eISSN

1090-2104

DOI

10.1016/j.bbrc.2025.152046

WoS UID

WOS:001498451900001