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

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