Targeting PGAM1 Y119 Phosphorylation Resensitizes Non-Small Cell Lung Cancer to Cisplatin Therapy by Promoting Oxidative Stress and DNA Damage

Cisplatin resistance remains a primary challenge in the clinical management of non-small cell lung cancer (NSCLC), yet the regulatory targets underlying this resistance remain largely unknown. It is well established that cisplatin kills tumor cells through the induction of DNA damage and the accumulation of reactive oxygen species (ROS), which exacerbate DNA damage. Here, we identify the glycolytic metabolic enzyme PGAM1, and specifically its elevated activity in cisplatin-resistant tumors, as a pivotal metabolic driver of this resistance. Y119 phosphorylation, which reflects increased PGAM1 activity, is significantly elevated in NSCLC patient tissues and further amplified in cisplatin-resistant cell lines. Mutation of the PGAM1 Y119 phosphorylation site (Y119F) resensitizes resistant cells to cisplatin both in vitro and in vivo. Mechanistically, Y119-phosphorylated PGAM1 enhances flux through the pentose phosphate pathway (PPP) and the serine synthesis pathway (SSP). This metabolic reprogramming promotes nucleotide biosynthesis and NADPH generation, thereby alleviating cisplatin-induced DNA damage and oxidative stress. In vivo, a PGAM1-derived pY119-mimetic cell-permeable peptide (Y119E-TAT) that competitively disrupts PGAM1 binding to its histidine kinase, thereby inhibiting PGAM1 activity, potently inhibits cisplatin-resistant NSCLC tumor growth. Together, these findings reveal a novel mechanism by which PGAM1 Y119 phosphorylation drives chemoresistance and suggest that targeting this phosphorylation event represents a potential therapeutic strategy to overcome cisplatin resistance in NSCLC.