Mitochondrial ClpX Inhibition Induces Ferroptosis and Blocks Pancreatic Cancer Cell Proliferation.

The ATPase caseinolytic protease X (ClpX), forming the ClpXP complex with caseinolytic protease P (ClpP), is essential for mitochondrial protein homeostasis. While ClpP targeting is a recognized anticancer strategy, the role of ClpX in cancer remains underexplored. In pancreatic ductal adenocarcinoma (PDAC), elevated CLPX expression correlates with poor prognosis, suggesting its oncogenic function. CLPX knockdown disrupts mitochondrial homeostasis, and reduces oxidative phosphorylation, thus leading to mitochondrial dysfunction and impaired PDAC cell proliferation. The ClpX-mediated mitochondrial dysfunction induces oxidative stress, unfolded protein response (UPR), and ferroptosis, which is evidenced by increased reactive oxygen species, ferrous iron, lipid peroxidation, and malondialdehyde levels. Screening ATPase inhibitors identifies MSC1094308 as a hit compound for ClpX inhibition, which suppresses ClpXP activity and induces UPR and ferroptosis in PDAC cells. These findings highlight ClpX inhibition as a promising therapeutic strategy for PDAC.