Aberrant ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma

Targeting the mitochondrial caseinolytic protease P (ClpP) is a potential novel strategy for treating leukemia. However, little is known about the therapeutic effects of ClpP in solid tumors. In this study, we identify a strong activator of the mitochondrial ClpP for subsequent use in targeted pancreatic ductal adenocarcinoma (PDAC) therapy. Analysis of clinical data demonstrated a positive association between ClpP expression and prognosis in PDAC patients. We validated that aberrant ClpP activation can lead to growth arrest in PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization to develop a potent ClpP activator, ZG111, which promoted ClpP to degrade respiratory chain complexes and occurred in a ClpP-dependent manner. This resulted in impaired oxidative phosphorylation in the mitochondria and activation of JNK/c-Jun pathway and endoplasmic reticulum stress response. ZG111 also produced significant antitumor effects on tumors in cell-derived and patient-derived xenografted mice models. Altogether, our identification of ZG111 demonstrated that the aberrant activation of ClpP hydrolysis can be used as a potential therapeutic strategy to treat PDAC cancer. Overall design: Examination of ZG111 , DMSO treatment, Y118A ClpP activation,or vehicle control on the transcriptional inluences in BxPC-3 cells.