Deciphering the Role of AlaRS in Head and Neck Cancer by Targeting the AlaRS-Mortalin-PARP1 Axis with Chelerythrine for Therapeutic Intervention

Aminoacyl-tRNA synthetases (AARS) have been increasingly implicated in cancer, although the underlying mechanisms remain unclear. Our analysis reveals that alanyl-tRNA synthetase (AlaRS) is upregulated in head and neck squamous cell carcinoma (HNSCC) tumor cells, with higher expression correlating with shorter patient survival. The downregulation of AlaRS significantly inhibits HNSCC cell proliferation, suggesting its pivotal role in tumorigenesis. Through a multi-faceted screening approach, we identified chelerythrine (CHE) as a potent inhibitor of AlaRS. CHE binds to the substrate pocket of AlaRS, thereby inhibiting protein translation and disrupting the AlaRS-Mortalin-PARP1 ternary complex. This disruption decreases PARP1 and Mortalin levels, leading to increased CDKN1A/p21 expression, cell cycle arrest, and eventual cell death. In vivo studies further demonstrated the efficacy of CHE, significantly inhibiting tumor growth in a mouse xenograft model of HNSCC. These findings not only deepen our understanding of AlaRS's multifaceted role in HNSCC but also highlight the therapeutic potential of targeting AlaRS with CHE.