Abstract / Summary
ABSTRACT Trastuzumab is the standard first‐line targeted therapy for human epidermal growth factor receptor 2 (HER2)‐positive gastric cancer (GC). Unfortunately, its clinical efficacy is often compromised by the development of drug resistance. The Warburg effect, a hallmark of cancer metabolism, leads to substantial lactate accumulation. Nevertheless, the impact of metabolic reprogramming on the response to HER2‐targeted therapy remains poorly understood. Here, we demonstrate that AARS1‐mediated lactylation of HER2 promotes trastuzumab resistance in GC. Mechanistically, lactylation at lysine 1171 (K1171) promotes USP11‐mediated deubiquitination and stabilization of HER2 and also enhances the interaction between HER2 and EGFR. Clinically, elevated HER2 K1171 lactylation levels are associated with poor prognosis in GC patients. Inhibiting HER2 K1171 lactylation with L‐alanine or stiripentol—a lactate dehydrogenase inhibitor (LDHi) clinically approved for epilepsy—significantly sensitizes tumor cells to trastuzumab. Furthermore, a cell‐penetrating peptide designed to specifically block HER2 K1171 lactylation potently enhances antitumor efficacy in vivo. In summary, our findings identify HER2 lactylation as a critical mechanism underlying trastuzumab resistance and highlight lactate metabolism as a promising therapeutic target for HER2‐positive GC.