The role of Alanyl-tRNA synthetase 1 lactylation in tumors and other diseases

Tumorigenesis and progression are driven by dysregulated genes and signaling pathways, with cellular metabolic reprogramming being a hallmark that supports neoplastic growth. Alanyl-tRNA Synthetase 1 (AARS1), a key enzyme with dual roles in metabolism and gene expression regulation, has emerged as a critical focus in cancer and disease research. As a member of the aminoacyl-tRNA synthetase (AARS) family, AARS1 canonically catalyzes the attachment of alanine to its cognate transfer RNA (tRNA) to ensure fidelity in protein synthesis. Emerging evidence reveals non-canonical roles of AARS1 in tumor biology, including regulation of metabolic reprogramming, cell proliferation, apoptosis, and intracellular signal sensing-all of which directly impact tumor growth and patient prognosis. Beyond cancer, dysregulated AARS1 (via abnormal expression or pathogenic mutations) is linked to a spectrum of non-malignant disorders, including Charcot-Marie-Tooth (CMT) disease (a hereditary peripheral neuropathy), adult-onset leukoencephalopathy, recurrent acute liver failure, and sulfide dysplasia. These associations arise from disrupted cellular homeostasis and impaired physiological functions caused by AARS1-mediated pathway dysregulation. Notably, AARS1's ability to sense lactate and catalyze lysine lactylation-a newly identified post-translational modification (PTM)-represents a novel mechanism linking metabolic dysregulation to disease pathogenesis. Dysregulated AARS1 contributes to tumor initiation, progression, metastasis, and treatment resistance, while its mutations drive the onset of several neurodegenerative and metabolic disorders. Unraveling the molecular mechanisms of AARS1, particularly its lactylation-related functions, will deepen our understanding of cellular metabolism in disease and identify novel therapeutic targets for precise diagnosis and treatment of tumors and other disorders. Furthermore, AARS1 holds significant promise as a diagnostic biomarker and therapeutic target, offering new avenues for precision medicine in both oncology and non-malignant conditions.