SLC16A3 as a novel therapeutic target for overcoming radioresistance and chemoresistance in lung cancer.

Radiotherapy and chemotherapy are central components of lung cancer treatment. However, the development of therapeutic resistance significantly limits their efficacy. Here, we identified SLC16A3 as a potential biomarker associated with radioresistance and chemoresistance in lung cancer. Transcriptomic and protein analyses revealed significantly higher SLC16A3 expression in radioresistant R-H460 cells than in parental H460 cells, and immunohistochemistry further confirmed higher SLC16A3 expression in human lung tumors than in healthy tissues. Silencing SLC16A3 significantly reduced cell survival and promoted caspase-3-dependent apoptosis, which was further enhanced by ionizing radiation or cisplatin treatment. Phospho-kinase array profiling demonstrated activation of the p38-MAPK pathway upon SLC16A3 inhibition, and pharmacological blockade of p38 (SB203580) attenuated apoptosis, confirming that SLC16A3 knockdown-induced apoptosis is p38-dependent. Collectively, these findings uncover a previously unrecognized SLC16A3-p38-caspase signaling axis that promotes therapeutic resistance and highlight SLC16A3 as a promising therapeutic target for overcoming radioresistance and chemoresistance in lung cancer.