Diclofenac impairs autophagic flux via oxidative stress and lysosomal dysfunction: Implications for hepatotoxicity

Area of Science:

• Hepatology
• Cell Biology
• Toxicology

Background:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause severe side effects, including liver damage.
• Mitochondrial damage and oxidative stress are implicated in NSAID toxicity, but mechanisms remain unclear.

Purpose of the Study:

• To investigate the mechanisms underlying NSAID-induced hepatotoxicity.
• To determine the role of autophagy and lysosomal function in diclofenac toxicity.

Main Methods:

• Hepatocytes were treated with diclofenac to assess autophagic flux and lysosomal function.
• Reactive oxygen species (ROS) production, lysosomal pH, and cathepsin activity were measured.
• Mitochondrial ROS scavenging, clioquinol treatment, and rapamycin administration were used to evaluate protective effects.

Main Results:

• Diclofenac inhibited autophagic flux in hepatocytes by increasing lysosomal pH and blocking autophagosome-lysosome fusion.
• This lysosomal dysfunction was dependent on reactive oxygen species (ROS) production.
• Impaired autophagy led to compromised mitophagy and increased cellular ROS, contributing to diclofenac-induced cell death and hepatotoxicity.
• Rapamycin protected against diclofenac-induced hepatotoxicity.

Conclusions:

• Diclofenac induces hepatotoxicity by causing ROS-dependent lysosomal dysfunction and suppressing autophagy.
• Inhibition of autophagy impairs mitochondrial quality control, exacerbates oxidative stress, and leads to liver injury.
• Targeting lysosomal function and autophagy may offer therapeutic strategies for NSAID-induced liver damage.