Targeting PGAM1 overcomes paclitaxel resistance and restores cuproptosis sensitivity in non-small cell lung cancer.

Paclitaxel (PTX) resistance is a major obstacle in non-small cell lung cancer (NSCLC). The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is implicated in chemoresistance, but its role in PTX resistance and cuproptosis remains unknown. We analyzed PGAM1 expression in PTX-resistant NSCLC cells and patient cohorts, performed truncation mapping and co-immunoprecipitation, and evaluated the PGAM1/PP2A/AKT/β-catenin/ATP7B axis. Drug sensitivity and cuproptosis were assessed in vitro, in patient-derived organoids (PDOs), and in xenograft models using the PGAM1 inhibitor HKB99. We identified that PGAM1 is overexpressed in PTX-resistant NSCLC and correlates with poor prognosis. PGAM1 overexpression reduces PTX sensitivity and confers cuproptosis resistance. Mechanistically, PGAM1 binds PP2A via its 1-150 region (critical residues V81, R83, N135, D144), inhibiting PP2A and enhancing AKT/GSK3β phosphorylation. This stabilizes β-catenin and promotes its nuclear translocation, where β-catenin/TCF4 drives ATP7B transcription. Elevated ATP7B lowers intracellular copper, impairs DLAT oligomerization, and confers resistance to elesclomol-induced cuproptosis. Pharmacologic or genetic inhibition of PGAM1 restored PP2A activity, re-sensitized PTX-resistant NSCLC cells to paclitaxel, and re-engaged cuproptosis. These effects were rescued by reconstitution with wild-type PGAM1, but not with the PP2A-binding-deficient mutant, indicating that PTX resistance is driven by the scaffolding function of PGAM1. The therapeutic potential of this strategy was validated in PDOs and xenograft models, where HKB99 synergized with PTX to suppress the growth of resistant tumors. In conclusion, PGAM1 drives PTX resistance by enabling cuproptosis evasion through the PP2A/AKT/β-catenin/ATP7B axis; combining PGAM1 inhibition with PTX represents a promising strategy for refractory NSCLC.