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

ABSTRACT 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 Fe 2+ 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.