The Role of Ferroptosis and Cuproptosis in Tuberculosis Pathogenesis: Implications for Therapeutic Strategies.

Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) remains a global health crisis, with over 10 million people affected annually. Despite advancements in treatment, M.tb has developed mechanisms to evade host immune responses, complicating efforts to eradicate the disease. Two emerging cell death pathways, ferroptosis and cuproptosis, have been linked to TB pathogenesis. Ferroptosis, an iron-dependent form of cell death, is driven by lipid peroxidation and reactive oxygen species (ROS) accumulation. This process can limit M.tb replication by depleting intracellular iron and inducing macrophage necrosis. However, excessive ferroptosis may lead to tissue damage and aid bacterial dissemination. Cuproptosis, triggered by copper accumulation, disrupts mitochondrial metabolism, leading to protein aggregation and cell death. M.tb exploits both iron and copper metabolism to survive within macrophages, manipulating these processes to resist oxidative stress and immune responses. This review examines the roles of ferroptosis and cuproptosis in TB, discussing how M.tb manipulates these pathways for survival. While therapeutic strategies targeting these processes, such as ferroptosis inducers (Erastin, RSL3) and inhibitors (Ferrostatin-1) and copper ionophores (Disulfiram, Elesclomol) and chelators, show promise, the limited understanding of these pathways and potential off-target effects remains a significant challenge. Further exploration of these pathways may provide insights into the development of targeted therapies aimed at controlling M.tb infection while minimizing host tissue damage. By elucidating the complex interactions between ferroptosis, cuproptosis, and TB, future therapies could better address bacterial resistance and improve clinical outcomes.