Arginase 2 Promotes Colorectal Cancer Metastasis via PI3K/AKT Pathway Activation and Regulates Tumor Immune Infiltration

ABSTRACT Background Colorectal cancer (CRC) is a leading cause of cancer‐related deaths, with metabolic reprogramming involved in its pathogenesis. Aberrant Arginase 2 (ARG2) expression is linked to malignant progression, but its role in CRC remains unclear. Methods ARG2 expression in CRC and adjacent tissues was analyzed. In vitro experiments were performed after ARG2 knockdown. Mechanistic investigations focused on epithelial‐mesenchymal transition (EMT), PI3K/AKT pathway, immune infiltration, and drug sensitivity. Results ARG2 was upregulated in CRC tissues, correlating with poor prognosis. ARG2 knockdown inhibited CRC cell proliferation, migration, and invasion by reducing Zinc Finger E‐Box Binding Homeobox 1 (ZEB1), N‐cadherin, and MMP2, suppressing EMT. Additionally, ARG2 knockdown significantly inhibited the PI3K/AKT signaling pathway. Immune infiltration analysis revealed high ARG2 expression correlated with reduced activated B cells and macrophages. Drug sensitivity analysis indicated that high ARG2 expression was associated with decreased efficacy of certain chemotherapeutic agents. Conclusion ARG2 is an independent prognostic marker for CRC. It promotes CRC progression via regulating EMT and PI3K/AKT, holding potential as a novel diagnostic and therapeutic target.