Bufalin reverses oxaliplatin resistance in gastric cancer by targeting YBX1 to suppress glycolysis.

Oxaliplatin resistance is a key challenge in gastric cancer therapy. This study explored how bufalin, an active component of Chansu, reverses this resistance. We found that bufalin targets the transcription factor YBX1, which is upregulated in resistant cells. YBX1 activates STC1 expression, leading to PI3K/Akt pathway activation, increased HK2 levels, and enhanced glycolysis-all contributing to resistance. Bufalin inhibits this YBX1/STC1/glycolysis axis. Using in vitro assays (proliferation, apoptosis, glycolysis measurement) and in vivo models, we demonstrated that bufalin suppresses glycolysis and restores oxaliplatin sensitivity. Mechanistic studies (RNA-seq, ChIP, SPR, etc.) confirmed the direct YBX1-bufalin interaction. Our work reveals YBX1/STC1-mediated glycolysis as a novel resistance mechanism and identifies bufalin as a promising therapeutic agent to overcome it.