MAZ-driven MRPL11 links mitochondrial homeostasis to AKT/mTOR signaling and promotes pancreatic ductal adenocarcinoma progression.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, owing to late diagnosis, rapid progression, and resistance to therapy. Here, we identify mitochondrial ribosomal protein L11 (MRPL11) as a novel oncogenic driver of PDAC. Multi-omics and survival analyses revealed that MRPL11 is markedly upregulated in PDAC tissues and cell lines, and its elevated expression predicts poor overall survival (OS) and disease-free survival (DFS). Functional assays demonstrated that MRPL11 promotes proliferation, migration, invasion, and spheroid growth, whereas its depletion induces G1/S arrest, apoptosis, and sensitizes cells to parthenolide (PTL). Mechanistically, MRPL11 preserves mitochondrial homeostasis by maintaining ATP production, membrane potential, and oxidative phosphorylation (OXPHOS), while limiting the accumulation of reactive oxygen species (ROS). In addition, MRPL11 activates the AKT/mTOR pathway, and its transcription is directly regulated by the MYC-associated zinc finger protein‌ (MAZ). Rescue experiments confirmed that the MAZ-MRPL11 axis drives PDAC aggressiveness through AKT/mTOR activation. In vivo, MRPL11 knockdown significantly suppressed xenograft tumor growth and enhanced apoptosis. Collectively, these findings establish MRPL11 as a critical link between mitochondrial regulation and oncogenic signaling, underscoring its potential as a prognostic biomarker and a candidate molecule for further therapeutic investigation in PDAC.