Aars1, short for alanyl-tRNA synthetase 1, is not only involved in the canonical process of charging tRNA with alanine, but also has non-canonical functions. It has emerged as a key molecule in linking cellular metabolism to protein function, and is associated with multiple biological pathways, including those related to tumorigenesis and innate immunity [1,2,3]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, could potentially be valuable for further exploring its functions in vivo.

Recent studies have revealed several critical functions of Aars1. It acts as a lactate sensor and lactyltransferase. In tumor cells, Aars1 binds lactate, catalyzes lactate-AMP formation, and transfers lactate to lysine residues of target proteins. For example, it lactylates p53 at lysine 120 and 139 in the DNA-binding domain, hindering p53's liquid-liquid phase separation, DNA binding, and transcriptional activation, thus contributing to tumorigenesis [1]. Aars1 also senses L-lactate and mediates lysine lactylation of cyclic GMP-AMP synthase (cGAS), inactivating it in response to L-lactate [2]. In gastric cancer, Aars1 translocates into the nucleus upon sensing intracellular lactate, lactylates and activates the YAP-TEAD complex, and forms a positive-feedback loop with YAP-TEAD to promote cell proliferation [3].

In conclusion, Aars1 has diverse essential biological functions, especially in the context of cellular metabolism-related protein modification. Studies using KO/CKO mouse models (not explicitly described in the provided references but potentially valuable) could further clarify its role in tumorigenesis, innate immunity, and other disease-related processes, providing insights into the underlying molecular mechanisms and potential therapeutic targets.