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ClpX inhibition promotes ferroptosis through mitochondrial dysfunction to suppress pancreatic ductal adenocarcinoma progression

ABSTRACT: Caseinolytic protease X (ClpX) is an unfoldase that forms the ClpXP complex with caseinolytic protease P (ClpP), playing a critical role in maintaining mitochondrial protein homeostasis. While targeting ClpP has emerged as a promising cancer intervention strategy, the biological function of ClpX in cancer remains largely unexplored. In this study, we identify elevated expression of CLPX in pancreatic ductal adenocarcinoma (PDAC), which correlates with poor patient prognosis. CLPX knockdown significantly inhibits cell proliferation and disrupts mitochondrial protein homeostasis in PDAC cells. This knockdown also induces mitochondrial oxidative stress, impairs oxidative phosphorylation, and activates the unfolded protein response. CLPX knockdown increases reactive oxygen species (ROS) levels, ferrous ion accumulation, lipid peroxidation, and elevates malonaldehyde content, thus promoting ferroptosis. Furthermore, screening of reported ATPase inhibitors reveals that MSC1094308 binds to ClpX, inhibiting ClpXP-mediated substrate degradation. MSC1094308 induces unfolded protein stress and ferroptosis in PDAC cells. Altogether, our findings suggest that ClpX inhibition represents a potent therapeutic strategy for combating PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289242 | GEO | 2026/01/28

REPOSITORIES: GEO

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Project description:The peptidase ClpP is conserved from bacteria to human. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder. Because of its known relevance for the mitochondrial unfolded protein response during cell stress, we characterized two ClpP knock-out mouse founder lines and documented similar phenotypes. Ubiquitously, ClpP absence led to accumulation of its interactor protein ClpX without transcript upregulation. Interestingly, most wild-type tissues with substantial ClpP amounts had no detectable ClpX. This inverse correlation suggests that ClpX levels and degradation are regulated by ClpP. The expectation of similar protein levels, in view of a reported association of heptameric ClpP rings with hexameric ClpX rings, was confirmed only in testis of wild-type animals. Germline tissue was exceptional also in its vulnerability to ClpP deletion, with both founder lines showing complete infertility for males and females. Otherwise, ubiquitous mitochondrial dysfunction was apparent from severe growth retardation and reduced spontaneous motor activity of the animals, and from a pronounced decrease in pre-/postnatal survival. Spermatogenesis was found aborted at the spermatid stage, acrosomes and axonemes were not formed. Overall, tissue-specific roles of ClpP were evident by this massive effect for germ cells, mild bioenergetic deficits in muscle and liver tissues, and excellent compensation in brain. ClpX was previously reported to chaperone unfolded proteins and also DNA condensation in mitochondria, so it is likely that this pathway is particularly susceptible in germ cells. In conclusion, our study indicates that the role of ClpP in quality control is indispensable during development for cells with rapid changes of mitochondrial numbers, and is relevant during aging for growth and survival of the organism. Factorial design comparing ClpP knock-out mice with wild type littermates in five different tissues (brain, testis, liver, skeletal and heart muscle)

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ClpX inhibition promotes ferroptosis through mitochondrial dysfunction to suppress pancreatic ductal adenocarcinoma progression

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