Mitoxantrone Activates IL-8 Dependent NF-κB Signalling Cascade to Elevate Mitochondrial Calcium and ROS, Triggering Mitophagy and Promoting Mycobacterial Clearance in dTHP-1 Cells

Abstract

Mitoxantrone, a topoisomerase II inhibitor with known immunomodulatory properties, has emerged as a potential regulator of mitochondrial quality control in macrophages In this study, we explored the role of NF κB IL 8 signalling in mitoxantrone mediated mitochondrial responses and its impact on mycobacterial clearance in differentiated THP 1 cells Our findings suggest that mitoxantrone triggers IL 8 activation, leading to upregulation of NF κB expression The autocrine IL 8 signalling promotes a rise in mitochondrial calcium levels, accompanied by increased generation of mitochondrial reactive oxygen species These mitochondrial changes facilitate the initiation of mitophagy, a selective form of autophagy responsible for the removal of damaged mitochondria The induction of mitophagy was further correlated with enhanced bactericidal activity against intracellular mycobacterium, indicating a link between drug induced mitochondrial stress and host defense mechanisms Overall, the study highlights a novel immunometabolic pathway through which mitoxantrone modulates IL 8 driven PI 3 K Akt NF κB signalling to coordinate mitochondrial calcium ROS dynamics and mitophagy activation These findings provide new insight into the immunotherapeutic potential of mitoxantrone in augmenting macrophage mediated defense responses against mycobacterial infection.