Mefenamic Acid-Upregulated Nrf2/SQSTM1 Protects Hepatocytes against Oxidative Stress-Induced Cell Damage

Area of Science:

• Pharmacology
• Cell Biology
• Toxicology

Background:

• Mefenamic acid (MFA) is a non-steroidal anti-inflammatory drug (NSAID) with known antioxidant and neuroprotective properties.
• The specific impact of MFA on liver cells and its underlying antioxidative mechanisms remain unclear.

Purpose of the Study:

• To investigate the antioxidative effects of MFA in liver cells.
• To elucidate the molecular mechanisms responsible for MFA's protective actions against oxidative stress.

Main Methods:

• HepG2 cells were treated with MFA, and the expression of Nrf2 pathway components and SQSTM1 was analyzed.
• Experiments involving SQSTM1 knockdown were performed to assess its role in MFA's effects.
• Cytotoxicity was induced using tert-Butyl hydroperoxide (tBHP) to evaluate MFA's protective capacity.

Main Results:

• MFA treatment upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by disrupting the Keap1-Nrf2 interaction.
• MFA increased sequestosome 1 (SQSTM1) expression in HepG2 cells, and this effect was dependent on SQSTM1.
• MFA protected HepG2 cells against tert-Butyl hydroperoxide (tBHP)-induced cytotoxicity, an effect abolished by SQSTM1 knockdown.

Conclusions:

• Mefenamic acid exhibits cytoprotective effects against oxidative stress in liver cells.
• These protective effects are mediated through the upregulation of SQSTM1 and subsequent activation of the Nrf2 signaling pathway.
• MFA shows potential as a therapeutic agent for conditions involving oxidative stress.