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

Sep 23, 2026

Chemoresistance undermines colorectal cancer treatment, and metabolic reprogramming is a key hallmark involving the pentose phosphate pathway (PPP). This study investigates the long noncoding RNA MAFG-AS1 in CRC chemoresistance and its mechanism. TCGA analysis and multiple functional assays show that MAFG-AS1 is upregulated by c-Myc, binds and stabilizes G6PD homodimers, activates PPP flux, elevates NADPH, lowers ROS, and promotes proliferation and tumor growth. MAFG-AS1 knockdown increases sensitivity to cisplatin and oxaliplatin.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusion

Materials and methods

Cell culture

siRNA and shRNA oligos

Inducible shRNA knockdown

Plasmids

Quantitative PCR (qPCR)

Kou etal. Journal of Translational Medicine (2026) 24:517 [https://doi.org/10.1186/s12967-026-08048-7](https://doi.org/10.1186/s12967-026-08048-7) Journal of Translational Medicine RESEARCH Open Access The MAFG-AS1/G6PD axis reduces platinum sensitivity in colorectal cancer through pentose phosphate pathway activation Jia Hui Kou1†, Yujie Yao2†, Wen Jin Li1†, Jiajie Zou1, Luke Kong1, Junqi Zheng3, Yi Meng Yue4, Man Man Han4 and Su Tang Guo2* Abstract 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. Keywords MAFG-AS1, G6PD, ROS, Pentose phosphate pathway, lncRNA †Jia Hui Kou, Yujie Yao and Wen Jin Li contributed equally to this work. *Correspondence: Su Tang Guo [sutangguo@aliyun.com](sutangguo@aliyun.com) 1School of Basic Medical Science, Shanxi Medical University, Taiyuan 030000, China 2Central Laboratory, Shanxi Province Cancer Hospital and Cancer Hospital Affiliated to Shanxi Medical University, Chinese Academy of Medical Sciences and Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030000, China 3Taiyuan Central Hospital, Taiyuan 030000, China 4Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China Materials and methods Cell culture Human colon adenocarcinoma (COAD) cell lines (HCT116, HT29, RKO, SW480, Caco2, WiDr) and the immortalized nonmalignant colorectal epithelial line NCM460 were cultured in DMEM at 37 °C with 5% CO₂. All cell lines (Supplementary Table 1) were regularly tested for mycoplasma contamination by PCR and authenticated by STR profiling. Cells within 15 passages after thawing were used for experiments. Formalin-fixed paraffin-embedded COAD tissues and matched adjacent normal tissues were obtained from the Shanxi Cancer Hospital Biobank. © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy o

FAQs

What problem does the study address in colorectal cancer therapy?

The study targets chemoresistance in colorectal cancer, which limits the effectiveness of platinum-based treatment.

How does MAFG-AS1 affect the pentose phosphate pathway and redox balance?

MAFG-AS1 enhances G6PD-dependent PPP activity, increases NADPH production, reduces ROS levels, and maintains redox homeostasis.

What is the impact of reducing MAFG-AS1 on platinum drug response?

MAFG-AS1 knockdown sensitizes CRC cells to cisplatin and oxaliplatin, indicating improved platinum efficacy.

Sep 23, 2026

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