KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.

KRAS is the most frequently mutated oncogene in human cancers, and its G12C variant is highly prevalent in lung adenocarcinoma (LUAD) and predicts poor clinical outcomes. However, the metabolic mechanisms underlying KRAS-driven malignancy and therapeutic resistance remain incompletely understood. Here, we identify alanyl-tRNA synthetase 1 (AARS1) as a previously unrecognized metabolic effector of KRAS signaling. AARS1 protein-but not its mRNA-is markedly upregulated in LUAD tissues, owing to impaired selective autophagic degradation mediated by the E3 ligase TRIM21. Mechanistically, KRAS G12C activates ERK2-dependent phosphorylation of AARS1 at Ser882, disrupting its interaction with TRIM21 and preventing autophagic turnover. Stabilized AARS1 drives metabolic reprogramming by catalyzing lysine lactylation of PDHA1 (K336) and ENO1 (K71), thereby suppressing OXPHOS, enhancing glycolysis, and promoting tumor progression. Importantly, KRAS G12C-induced AARS1 phosphorylation confers resistance to Sorafenib. Blocking AARS1 phosphorylation using the natural compound Hypericin restores autophagic degradation of AARS1, reverses metabolic reprogramming, and markedly sensitizes KRAS-mutant LUAD organoids and PDX models to Sorafenib. These findings uncover AARS1 as a lactate-sensing oncogenic effector downstream of KRAS G12C and highlight the therapeutic potential of targeting AARS1 phosphorylation to overcome drug resistance in LUAD.