The MAFG-AS1/G6PD axis reduces platinum sensitivity in colorectal cancer through pentose phosphate pathway activation.

BACKGROUND: Chemoresistance remains a major challenge in colorectal cancer (CRC) treatment. Metabolic reprogramming is a cancer hallmark, with the pentose phosphate pathway (PPP) playing a ceral role. This study aimed to investigate the role of the long noncoding RNA MAFG-AS1 in CRC chemoresistance and its underlying mechanism. METHODS: MAFG-AS1 expression was analyzed using TCGA data. Functional roles were assessed via RNA interference, overexpression, RNA pull-down, RIP, metabolic flux analysis, isotope tracing, and xenograft models, combined with qPCR, Western blot, flow cytometry, and IHC. Statistical analyses used t-tests and ANOVA. RESULTS: MAFG-AS1 was upregulated in CRC, driven transcriptionally by c-Myc. It directly bound to and stabilized G6PD homodimers, enhancing its enzymatic activity. This activated the PPP, increased NADPH production, reduced ROS levels, maintained redox homeostasis, and promoted CRC cell proliferation and tumor growth. MAFG-AS1 knockdown sensitized CRC cells to cisplatin and oxaliplatin. CONCLUSION: MAFG-AS1 promotes metabolic reprogramming and reduces platinum sensitivity in CRC by enhancing G6PD-dependent PPP flux and redox buffering capacity. Targeting the MAFG-AS1–G6PD axis may represent a potential strategy to improve the efficacy of platinum-based chemotherapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-08048-7.