Therapeutic targeting LRPPRC-mediated OXPHOS synthesis for cancer intervention

Oxidative phosphorylation (OXPHOS) is essential for the progression of tumors and their resistance to therapy. Conventional inhibitors of OXPHOS that directly target the electron transport chain (ETC) activity often lack tumor selectivity and demonstrate limited efficacy. Inhibiting mitochondrial gene expression to block the de novo biogenesis of OXPHOS complexes, rather than inhibiting pre-existing OXPHOS complexes, represents a more potent and tumor-selective strategy. This strategy highlights leucine-rich pentatricopeptide repeat-containing (LRPPRC) as a promising anticancer target.

Extensive evidence confirms that LRPPRC is commonly overexpressed in various cancer types and is indispensable for maintaining malignant phenotypes. Mechanistically, LRPPRC binds mitochondrial mRNAs (mt-mRNAs) via its pentatricopeptide repeat (PPR) motif-rich RNA-binding domain. By stabilizing mt-mRNA and enhancing its translational efficiency, LRPPRC facilitates OXPHOS complex biogenesis and OXPHOS in tumors. We have developed the first small-molecule screening platform targeting LRPPRC. Using this platform, we identified dual-function compounds that both inhibit LRPPRC's RNA-binding function and trigger its proteolytic degradation. These agents demonstrate potent suppression of OXPHOS and exhibit favorable safety profiles across multiple preclinical models.

Current LRPPRC inhibitors often suffer from suboptimal specificity and binding affinity. Advancing clinical translation requires co-crystal structures of LRPPRC for rational drug design and novel delivery strategies to enhance mitochondrial enrichment of inhibitors.