AlaRS-mediated lactylation shields PARP1 from ubiquitination to promote HNSCC progression

Abstract

Abstract textMetabolic reprogramming in solid tumors causes massive lactate accumulation, yet how this drives oncogenesis remains incompletely understood. Here, we identify alanyl-tRNA synthetase (AlaRS) as a cellular lactyltransferase that promotes head and neck squamous cell carcinoma (HNSCC) progression. AlaRS directly catalyzes site-specific lactylation of the DNA repair protein PARP1 at lysines K249 and K667. Crucially, we uncover a competitive post-translational crosstalk wherein this lactylation directly antagonizes PARP1 ubiquitination. This "lactyl-shield" prevents proteasomal degradation, hyper-stabilizing the PARP1-Mortalin complex and sustaining tumor proliferation via p53/p21 dysregulation. To therapeutically exploit this mechanism, we identified chelerythrine (CHE) as a potent, selective inhibitor that directly binds the AlaRS catalytic center. CHE abrogates AlaRS lactyltransferase activity, destabilizes PARP1, and robustly suppresses HNSCC xenograft growth in vivo. These findings establish a novel metabolic-post-translational axis linking lactate accumulation to oncoprotein stabilization, providing a blueprint for targeting tRNA synthetase moonlighting functions in cancer.