Matrine targets Enolase 1 and regulates the glycolysis-lactylation axis to enhance cisplatin sensitivity in triple-negative breast cancer.

INTRODUCTION: Matrine, a tetracyclic quinolizidine alkaloid derived from Sophora flavescens Aiton, exhibits potent antitumor activity. However, its direct molecular targets and the mechanisms by which it reverses chemoresistance in triple-negative breast cancer (TNBC) remain poorly defined.

OBJECTIVES: To investigate the molecular mechanism by which matrine in reversing cisplatin (CDDP) resistance in TNBC.

METHODS: The enhancing effects of matrine on CDDP sensitivity were evaluated in vitro and in BALB/c nude mouse xenografts. Molecular targets were identified via limited proteolysis-mass spectrometry (LiP-MS), followed by functional analyses of glycolysis, protein lactylation, and DNA repair.

RESULTS: Matrine significantly sensitized CDDP-resistant TNBC cells to apoptosis and inhibited tumor growth in vivo. Mechanistically, matrine directly targeted Enolase 1 (ENO1), disrupting its interaction with PGK1 and PGAM1. This interference suppressed glycolytic enzyme complex formation, thereby reducing glycolytic flux and protein lactylation. Attenuated lactylation subsequently impaired the assembly of the NBS1-RAD50-MRE11 DNA repair complex and downregulated resistance-associated transcription factors YY1 and YBX1. Importantly, ENO1 overexpression or exogenous sodium lactate supplementation rescued cells from matrine-mediated sensitization. In vivo results confirmed that matrine targets ENO1 to inhibit glycolysis and lactate production, thereby enhancing CDDP efficacy in resistant tumors.

CONCLUSIONS: Matrine reverses TNBC chemoresistance by targeting ENO1 to suppress the glycolysis-lactylation-DNA repair axis. These findings highlight the therapeutic potential of this traditional Chinese medicine derived compound in overcoming cancer drug resistance.