Mitophagy-mtROS axis contributes to anti-tuberculosis-induced liver injury through activation of the cGAS-STING pathway in rat hepatocytes

Tuberculosis (TB) remains a major worldwide healthcare issue, with anti-TB drugs playing a pivotal role in its treatment. However, the emergence of anti-TB drug-induced liver injury (ATB-DILI) poses a considerable challenge, undermining treatment efficacy and patient survival. This study investigates the underlying mechanisms of ATB-DILI, focusing on reactive oxygen species (ROS), mitophagy, lysosomal function, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. A rat hepatocyte model treated with standard anti-TB drugs was established to assess liver inflammation, oxidative stress biomarkers, mitochondrial function, and mitophagy processes. The results indicate that anti-TB drug administration induced significant inflammatory injury, characterized by elevated IL-6 and reduced IL-4 and IL-10 levels. ROS overproduction predominantly originates in the mitochondrial level, consequently resulting in oxidative stress and impaired mitochondrial function. A noticeable decline in both the oxygen consumption rate and ATP production is indicative of this phenomenon. Although mitophagy was activated, impaired lysosomal function hindered mitophagic flux, leading to the buildup of damaged mitochondria and ROS. Pharmacological intervention with mitoTEMPO alleviated mitochondrial dysfunction, while clioquinol restored lysosomal function and improved mitophagy. Additionally, the cGAS-STING signaling pathway was found to regulate inflammation in ATB-DILI, with both mitoTEMPO and clioquinol alleviating its effects. These findings elucidate the crucial impact of lysosome-mediated mitophagy dysfunction and mitochondrial ROS in ATB-DILI, highlighting potential therapeutic targets to enhance liver protection during anti-TB treatment.