Cancer associated fibroblast-related lactate metabolism promotes cisplatin resistance in colorectal cancer by enhancing NBS1 transcription via H3K18 lactylation

Background Cancer-associated fibroblasts (CAFs) secrete abundant lactate and drive chemoresistance in colorectal cancer (CRC). This study investigates the epigenetic mechanisms, focusing on histone lactylation and transcriptional regulation of Nijmegen breakage syndrome 1 (NBS1). Methods Clinical analyses included 32 cisplatin (DDP)-resistant and 37 DDP-sensitive CRC specimens to evaluate α-SMA-positive stromal signal, Histone H3 lysine 18 lactylation (H3K18la) and NBS1 expression. Mechanistic and functional experiments were primarily performed in HCT116 cells. Primary CAFs were co-cultured with HCT116 cells, with or without AZD3965, an inhibitor of the lactate transportermonocarboxylate transporter 1 (MCT1). Cell viability, apoptosis, half-maximal inhibitory concentration (IC 50 ), and the p300/H3K18la/NBS1 transcriptional axis were assessed. For in vivo validation, HCT116 cells (with or without NBS1 knockdown) were co-injected with CAFs into a xenograft mouse model (n = 6/group) receiving DDP treatment. Results In clinical samples, DDP-resistant tumors showed significantly higher α-SMA-positive stromal signal, H3K18la, and NBS1 levels than sensitive tumors, showing positive pairwise associations (r = 0.7744-0.7960). In vitro, CAF co-culture increased lactate production and HCT116 cisplatin IC 50 from 5.25 μM (95% CI: 4.88-5.65) to 13.88 μM (95% CI: 12.65-15.24), while suppressing apoptosis. These chemoprotective effects were significantly attenuated by AZD3965, which reduced the IC50 to 5.97 μM (95% CI: 5.35-6.67). Mechanistically, CAF-associated lactate promoted H3K18la enrichment at the NBS1 promoter, which was associated with transcriptional activation of NBS1. Rescue experiments showed that NBS1 knockdown significantly attenuated CAF-induced DDP resistance and restored apoptosis. In vivo, CAF co-injection promoted tumor progression under DDP treatment, which was effectively attenuated by NBS1 knockdown. Conclusion These preclinical findings demonstrate that CAF-associated, AZD3965-sensitive lactate signaling is associated with H3K18la enrichment and NBS1 upregulation, thereby reducing cisplatin sensitivity in CRC. Further pharmacological validation in independent models is required before translating these targets clinically.