Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors

Osteopontin (OPN), a key extracellular matrix protein, promotes gastrointestinal tumor progression by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. OPN enhances tumor proliferation and survival through mechanistic target of rapamycin and B-cell lymphoma 2 upregulation (<i>e.g.</i>, <i>via</i> denticleless E3 ubiquitin protein ligase homolog in hepatocellular carcinoma) and drives metastasis <i>via</i> PI3K/AKT-mediated epithelial-mesenchymal transition and androgen receptor (AR) activation (<i>e.g.</i>, <i>via</i> the OPN-RAN-AR axis in pancreatic cancer). Additionally, OPN induces chemoresistance by activating anti-apoptotic proteins (<i>e.g.</i>, XIAP <i>via</i> CXCR3/PI3K/AKT in colorectal cancer) and remodels the tumor microenvironment through VEGF-dependent angiogenesis and cluster of differentiation 44-PI3K/AKT-mediated immune evasion. Its interaction with TLR4, WNT, and other pathways amplifies oncogenic effects. Therapies targeting the OPN-PI3K/AKT axis (<i>e.g.</i>, PI3K inhibitors like LY294002) or combination treatments (<i>e.g.</i>, with EGFR-TKIs) show promise for reversing drug resistance. Future research should focus on OPN isoform specificity, clinical translation, and interactions with autophagy and long non-coding RNAs to refine precision therapies. This review summarizes recent advances in understanding the molecular mechanisms, therapeutic targets, and clinical challenges of the OPN-PI3K/AKT axis in gastrointestinal tumors, providing a foundation for overcoming resistance and developing precision therapies.