Abstract

Background Paclitaxel-based intraperitoneal chemotherapy (IPC) is a cornerstone strategy for treating gastric cancer peritoneal metastasis (GCPM). However, a subset of patients exhibit resistance to this therapy. Our study revealed that glucose transporter type 3 (GLUT3) is a key mediator of paclitaxel resistance in GCPM, although its precise mechanism of action remains to be fully elucidated. Methods Single-cell (nucleus) sequencing and immunohistochemical staining were used to analyze paclitaxel-resistant and paclitaxel-sensitive GCPM tissue samples. GLUT3 was knocked down in AGS and HGC27 cells and overexpressed in MKN45 cells to establish the corresponding experimental models. The CUT&Tag and ChIP-qPCR techniques were utilized to elucidate the GLUT3-histone H3 lysine 18 lactylation (H3K18la)-mitogen-activated protein kinase associated protein 1 (MAPKAP1) regulatory axis. A mouse peritoneal metastasis model was used to evaluate the ability of GLUT3 targeting to reverse ferroptosis resistance and paclitaxel chemoresistance. Results: GLUT3, glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) expression was significantly upregulated in paclitaxel-resistant GCPM tissues. Elevated GLUT3 expression correlated with poor prognosis in GC patients. Functionally, GLUT3 knockdown sensitized GC cells to both Erastin and paclitaxel, whereas GLUT3 overexpression conferred therapeutic resistance. Mechanistically, GLUT3 upregulated hexokinase 3 (HK3) expression, increasing glucose-6-phosphate (G6P) and lactate production. Elevated lactate levels supported E1A binding protein p300 (p300)-mediated H3K18la enrichment at the MAPKAP1 promoter, thereby activating its transcription. Rescue assays indicated that depletion of MAPKAP1 restored ferroptosis sensitivity in GC cells. In vivo , compared with paclitaxel monotherapy, the combination of GLUT3 inhibition and paclitaxel not only reduced tumor weight by 75.47% ( P<0.05 ) but also significantly suppre