Mechanism of AGEs-RAGE axis inhibition of ferroptosis in type 2 diabetic colon cancer by regulatory CEACAM1.

Type 2 diabetes mellitus (T2DM) patients with colon cancer have an increased incidence and poor prognosis, which may be closely related to advanced glycation end products (AGEs) and its receptor (RAGE), but the underlying mechanism is still unclear. The aim of this study is to investigate how the AGEs-RAGE axis inhibits ferroptosis in T2DM-associated colon cancer by regulating carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ELISA and Western blot were used to detect expression levels of CEACAM1 in 155 patients with colon cancer. In vitro experiments examined various parameters in CEACAM1 knockdown/overexpression cells co-cultured with AGEs. The molecular mechanism was validated using multiple detection methods following intervention with FPS-ZM1 and sabatolimab. Serum and tissue analyses revealed that CEACAM1 is up-regulated in colon cancer patients with T2DM. The AGEs-RAGE promotes colon cancer cell proliferation, migration and invasion by upregulating CEACAM1. CEACAM1 overexpression triggers IFN-γ pathway, thereby enhancing SLC7A11/GPX4-mediated ferroptosis resistance. Blockade of RAGE with FPS-ZM1 reverses CEACAM1 driven inhibition of ferroptosis by reducing GPX4. A nude mouse model of type 2 diabetic tumors was established to assess tumor growth. Furthermore, blockade of Tim-3 by sabatolimab disrupts its interaction with CEACAM1, restoring ferroptosis sensitivity and inhibiting subcutaneous tumor growth in these mice. The AGEs-RAGE axis inhibits ferroptosis by driving CEACAM1 overexpression and mediating IFN-γ/SLC7A11/GPX4 signaling pathway, which reveals a new mechanism by which AGEs-RAGE-CEACAM1 promotes tumor survival in diabetic environment. Sabatolimab may provide a therapeutic strategy for colon cancer patients with T2DM.