LncRNA ALMS1‐IT1 modulates ferroptosis and immune evasion in colorectal cancer through activating STAT3

Abstract Colorectal cancer (CRC) represents a significant malignancy within the digestive system, characterized by high incidence and mortality rates. In recent years, molecular targeted therapy has been introduced as a supplementary strategy in CRC management, complementing traditional modalities such as surgery, radiation and chemotherapy. The identification of novel therapeutic targets for CRC remains critically important. Ferroptosis, a unique form of programmed cell death distinct from apoptosis and necrosis, is characterized by cellular damage resulting from iron‐induced lipid peroxidation, leading to cell death. This study utilizes a combination of bioinformatics analysis and clinical specimen validation to demonstrate that the long non‐coding RNA (lncRNA) ALMS1‐IT1 is significantly upregulated in CRC tissues and strongly associated with ferroptosis. Through a series of experimental investigations, we have determined that ALMS1‐IT1 negatively regulates ferroptosis in CRC cells, thereby promoting cancer growth and metastasis, acting as an oncogenic factor. Furthermore, we explored the molecular interactions of ALMS1‐IT1, revealing its role in activating STAT3 protein phosphorylation. This activation enhances the immune evasion capabilities of CRC cells. Rescue experiments indicated that STAT3 activation is essential for ALMS1‐IT1's suppression of ferroptosis, immune evasion and oncogenic behaviour in CRC. Our findings underscore the critical biological role of ALMS1‐IT1 in the progression of CRC and suggest its potential as a target for drug development.