Circ-0030167/IGF2BP1 Induces Mitophagy-Mediated Ferroptosis via HMOX1 mRNA Stabilization in Pancreatic Cancer.

Pancreatic cancer (PC) represents a highly aggressive malignancy characterized by a 5 year survival rate of less than 12%. Recent investigations suggest that mitophagy may constitute a potential therapeutic target for PC. This study aims to elucidate the molecular mechanisms underlying circ-0030167's regulation of PC, extending our prior investigations. mRNA sequencing analysis demonstrated significant enrichment of mitophagy-related signaling pathways in PC cells overexpressing circ-0030167. Integrated analysis utilizing RNA-binding protein (RBP) databases identified IGF2BP1 as a binding partner, a finding corroborated by RNA pull-down assays, RNA immunoprecipitation (RIP) experiments, and fluorescence in situ hybridization (FISH) validation. Cell-derived xenograft (CDX) assays confirmed that circ-0030167 enhances IGF2BP1 protein stability. Subsequent bioinformatic analysis combined with mRNA-seq data revealed HMOX1 as a downstream target gene within the circ-0030167/IGF2BP1-mediated mitophagy pathway. Functional assays measuring ferroptosis-related parameters-cell viability, reactive oxygen species (ROS) levels, malondialdehyde (MDA) content, and Fe2+ concentration-established that the circ-0030167/IGF2BP1 axis modulates mitophagy-mediated ferroptosis through HMOX1. Furthermore, in vivo animal studies demonstrated that circ-0030167 overexpression markedly suppresses PC tumor growth. In conclusion, our findings identify the circ-0030167/IGF2BP1/HMOX1 axis as a critical regulatory factor targeting mitochondria-mediated ferroptosis, thereby presenting a novel therapeutic target for PC combination therapies.