Lactylation of SLC26A3 in the acidic tumor microenvironment promotes malignant progression of colorectal carcinoma

Abstract The acidic tumor microenvironment provides the energy that drives the development of malignant tumors. High concentrations of lactic acid and H + are key features of the acidic tumor microenvironment, and lactylation has gradually been shown to play a significant role in tumor progression. The expression of solute carrier family 26 member 3 (SLC26A3) is closely related to the occurrence and development of colorectal cancer (CRC), but the specific molecular mechanisms remain unclear. We demonstrated that alterations in the acidic microenvironment and overexpression of SLC26A3 significantly inhibited CRC occurrence and progression in vivo. Our study indicates that SLC26A3 undergoes lactylation in the acidic tumor microenvironment, which decreases SLC26A3 stability and expression. SLC26A3 interacts with the RNA-binding proteins Hu antigen R (HuR) and CUG-binding protein 1 (CUGBP1). When SLC26A3 expression is reduced, its ability to bind to HuR/CUGBP1 is weakened. As a result, HuR and CUGBP1 more readily interact with a subset of oncogenic mRNAs, regulating their stability and influencing their expression, ultimately promoting malignant tumor progression. 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.