Abstract 1356: The lactylation of SLC26A3 in acidic micro-environment contributes to colorectal carcinoma malignant progression

A recently discovered post-translational modification, lactylation, can regulate the structure and function of proteins, influencing cellular functions and disease progression. However, its role in tumor progression remains unclear.This study explored the contribution of lactylation modification of solute carrier family 26 member 3 (SLC26A3) in acidic microenvironments to the malignant progression of colorectal carcinoma (CRC). The findings revealed that the acidic tumor microenvironment reduced the stability and expression of SLC26A3 by promoting its lactylation. co-IP experiment results showed SLC26A3 interacted with RNA-binding proteins HuR and CUGBP1, and when the expression of SLC26A3 was decreased, its binding capacity to HuR/CUGBP1 was weakened. This led to an increased interaction of HuR and CUGBP1 with a subset of oncogenic mRNAs, regulating their stability and expression, ultimately promoting the progression of malignant tumors. The study also indicated that the expression of SLC26A3 was negatively correlated with the expression of tumor stem cell markers, and low expression of SLC26A3 promoted the stemness of CRC cells. Furthermore, the expression of SLC26A3 affected the resistance to oxaliplatin (OXA), invasiveness, and migratory ability of CRC cells. In animal models, normalizing the tumor acidic microenvironment and inducing the expression of SLC26A3 inhibited the development of CRC.These findings highlight the role of SLC26A3 as a potential suppressor of CRC recurrence, drug resistance, and metastasis, providing new insights for improving the clinical treatment and prognosis of CRC. Citation Format: Chong Chen, Peishan Hu, Yufeng Chen. The lactylation of SLC26A3 in acidic micro-environment contributes to colorectal carcinoma malignant progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1356.