Slc16a4, also known as monocarboxylate transporter 4 (MCT4), is a crucial transporter for lactate. It is involved in maintaining intracellular pH homeostasis and plays a significant role in the pyruvate-lactate metabolic axis. Lactate transport by MCT4 is associated with multiple biological processes, including energy metabolism, immune regulation, and cell-cell communication [2,3]. Genetic models, such as knockout mouse models, have been instrumental in understanding its functions.

In LKB1-deficient lung adenocarcinoma, MCT4-dependent lactate secretion suppresses antitumor immunity. MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models, indicating its role in immunotherapy resistance [1]. In the context of cardiac hypertrophy and heart failure, a novel, highly potent MCT4 inhibitor mitigated hypertrophy in cultured cardiomyocytes and in mice, suggesting MCT4's involvement in this disease process [2]. In hepatocellular carcinoma, genetic or pharmacological inhibition of MCT4 using VB124 suppressed tumor growth in immunocompetent mice by enhancing CD8 + T cell infiltration and cytotoxicity [4]. Also, in type 2 diabetes-associated cardiac energy metabolism injury, inhibiting MCT4 alleviates myocardial oxidative stress, reduces inflammatory macrophage infiltration, and enhances cardiac function in diabetic mice [5].

In summary, Slc16a4 (MCT4) is essential for lactate-related biological functions. Studies using knockout mouse models have revealed its significance in diseases such as cancer, heart failure, and diabetes-related cardiomyopathy. These findings highlight its potential as a therapeutic target for treating these conditions.