An Integrative Approach to Autophagy and Oxidative Stress Pathways for Clinical Prediction in Colorectal Cancer: A Narrative Review

Authors

  • Welly Hartono Ruslim Doctoral Program in Biomedical Sciences, YARSI University, Jakarta, Indonesia
  • Himmi Marsiati Graduate School, Doctoral Program in Biomedical Sciences, YARSI University, Jakarta, Indonesia
  • Nunung Ainur Rahmah Faculty of Medicine, YARSI University, Jakarta, Indonesia
  • Wifanto Saditya Jeo Division of Digestive Surgery, Faculty of Medicine, Indonesia University, Jakarta, Indonesia

DOI:

https://doi.org/10.38035/ijphs.v4i3.2264

Keywords:

Autophagy, Biomarkers, Colorectal Cancer, Oxidative Stress, Prognosis

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Increasing evidence suggests that oxidative stress and autophagy are interconnected biological processes involved in tumor initiation, progression, therapeutic resistance, and patient survival. However, their combined role as an integrated prognostic biomarker panel has not been comprehensively reviewed. This narrative review aimed to summarize current evidence on the interaction between oxidative stress and autophagy pathways and to evaluate the clinical potential of their biomarkers for prognostic prediction in CRC. This review was based on peer-reviewed open access publications from major scientific databases between 2019 and 2025. Studies that have assessed oxidative stress biomarkers, such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), nuclear factor erythroid 2-related factor 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and autophagy-related biomarkers, including microtubule-associated protein 1 light chain 3 beta (LC3B) and sequestosome 1 (p62/SQSTM1) were critically synthesized. Current evidence suggests a role for oxidative stress and autophagy dysregulation in the development of CRC. Increased expression of LC3B, p62/SQSTM1, NRF2, and 8-OHdG is always associated with advanced disease, treatment resistance, tumor recurrence, and poor overall survival. Integrating biomarkers from both pathways appears to improve prognostic accuracy compared with individual biomarkers. Combined assessment of oxidative stress and autophagy biomarkers represents a promising prognostic approach for CRC. Nevertheless, large prospective studies are required to validate their clinical utility before routine implementation in precision oncology.

References

Abugable, A. A., Antar, S., & El-Khamisy, S. F. (2024). Chromosomal single-strand break repair and neurological disease: Implications on transcription and emerging genomic tools. DNA Repair, 135, 103629. https://doi.org/10.1016/j.dnarep.2024.103629

Brandl, N., Seitz, R., Sendtner, N., Müller, M., & Gülow, K. (2025). Living on the Edge: ROS Homeostasis in Cancer Cells and Its Potential as a Therapeutic Target. Antioxidants, 14(8), 1002. https://doi.org/10.3390/antiox14081002

Cabrera-Serrano, A. J., Sánchez-Maldonado, J. M., González-Olmedo, C., Carretero-Fernández, M., Díaz-Beltrán, L., Gutiérrez-Bautista, J. F., García-Verdejo, F. J., Gálvez-Montosa, F., López-López, J. A., García-Martín, P., Pérez, E. M., Sánchez-Rovira, P., Reyes-Zurita, F. J., & Sainz, J. (2025). Crosstalk Between Autophagy and Oxidative Stress in Hematological Malignancies: Mechanisms, Implications, and Therapeutic Potential. Antioxidants, 14(3), 264. https://doi.org/10.3390/antiox14030264

Caldecott, K. W. (2024). Causes and consequences of DNA single-strand breaks. Trends in Biochemical Sciences, 49(1), 68–78. https://doi.org/10.1016/j.tibs.2023.11.001

Carretero-Fernández, M., Cabrera-Serrano, A. J., Sánchez-Maldonado, J. M., Ruiz-Durán, L., Jiménez-Romera, F., García-Verdejo, F. J., González-Olmedo, C., Cardús, A., Díaz-Beltrán, L., Gutiérrez-Bautista, J. F., Benavente, Y., Gálvez-Montosa, F., López-López, J. A., García-Martín, P., Pérez, E. M., Rodríguez-Sevilla, J. J., Casabonne, D., Sánchez-Rovira, P., Reyes-Zurita, F. J., & Sainz, J. (2025). Autophagy and oxidative stress in solid tumors: Mechanisms and therapeutic opportunities. Critical Reviews in Oncology/Hematology, 212, 104820. https://doi.org/10.1016/j.critrevonc.2025.104820

Catalano, T., Selvaggi, F., Cotellese, R., & Aceto, G. M. (2025). The Role of Reactive Oxygen Species in Colorectal Cancer Initiation and Progression: Perspectives on Theranostic Approaches. Cancers, 17(5), 752. https://doi.org/10.3390/cancers17050752

Cintoni, M., Palombaro, M., Zoli, E., D’Agostino, G., Pulcini, G., Leonardi, E., Raoul, P., Rinninella, E., De Maio, F., Capristo, E., Gasbarrini, A., & Mele, M. C. (2025). The Interplay Between the Gut Microbiota and Colorectal Cancer: A Review of the Literature. Microorganisms, 13(6), 1410. https://doi.org/10.3390/microorganisms13061410

Damiano, O. M., Stevens, A. J., Kenwright, D. N., & Seddon, A. R. (2025). Chronic Inflammation to Cancer: The Impact of Oxidative Stress on DNA Methylation. Frontiers in Bioscience-Landmark, 30(3). https://doi.org/10.31083/FBL26142

Dera, A. A., & Al Fayi, M. (2025). CB5712809, a novel Keap1 inhibitor upregulates SQSTM1/p62 mediated Nrf2 activation to induce cell death in colon cancer cells. Discover Oncology, 16(1), 981. https://doi.org/10.1007/s12672-025-02787-7

Hasan, A., Rizvi, S. F., Parveen, S., Pathak, N., Nazir, A., & Mir, S. S. (2022). Crosstalk Between ROS and Autophagy in Tumorigenesis: Understanding the Multifaceted Paradox. Frontiers in Oncology, 12. https://doi.org/10.3389/fonc.2022.852424

Hsu, W.-L., Wang, C.-M., Yao, C.-L., Chen, S.-C., Nien, C.-Y., Sun, Y.-H., Tseng, T.-Y., & Luo, Y.-H. (2022). Blockage of Nrf2 and autophagy by L-selenocystine induces selective death in Nrf2-addicted colorectal cancer cells through p62-Keap-1-Nrf2 axis. Cell Death & Disease, 13(12), 1060. https://doi.org/10.1038/s41419-022-05512-2

Huang, R.-X., & Zhou, P.-K. (2020). DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduction and Targeted Therapy, 5(1), 60. https://doi.org/10.1038/s41392-020-0150-x

Iqbal, M. J., Kabeer, A., Abbas, Z., Siddiqui, H. A., Calina, D., Sharifi-Rad, J., & Cho, W. C. (2024). Interplay of oxidative stress, cellular communication and signaling pathways in cancer. Cell Communication and Signaling, 22(1), 7. https://doi.org/10.1186/s12964-023-01398-5

Kang, M., Jeong, S., Park, S., Nam, S., Chung, J.-W., Kim, K. O., An, J., & Kim, J. H. (2023). Significance of 8-OHdG Expression as a Predictor of Survival in Colorectal Cancer. Cancers, 15(18), 4613. https://doi.org/10.3390/cancers15184613

Koustas, E., Sarantis, P., Trifylli, E.-M., Dikoglou-Tzanetatou, E., Ioakeimidou, E., Anastasiou, I. A., Karamouzis, M. V., & Theocharis, S. (2025). Autophagy and PXR Crosstalk in the Regulation of Cancer Drug Metabolism and Resistance According to Gene Mutational Status in Colorectal Cancer. Genes, 16(8), 892. https://doi.org/10.3390/genes16080892

Li, Z., Si, W., Jin, W., Yuan, Z., Chen, Y., & Fu, L. (2022). Targeting autophagy in colorectal cancer: An update on pharmacological small-molecule compounds. Drug Discovery Today, 27(8), 2373–2385. https://doi.org/10.1016/j.drudis.2022.05.011

Liang, X., Weng, J., You, Z., Wang, Y., Wen, J., Xia, Z., Huang, S., Luo, P., & Cheng, Q. (2025). Oxidative stress in cancer: from tumor and microenvironment remodeling to therapeutic frontiers. Molecular Cancer, 24(1), 219. https://doi.org/10.1186/s12943-025-02375-x

Ma, T.-F., Fan, Y.-R., Zhao, Y.-H., & Liu, B. (2023). Emerging role of autophagy in colorectal cancer: Progress and prospects for clinical intervention. World Journal of Gastrointestinal Oncology, 15(6), 979–987. https://doi.org/10.4251/wjgo.v15.i6.979

Nickoloff, J. A., Sharma, N., & Taylor, L. (2020). Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy. Genes, 11(1), 99. https://doi.org/10.3390/genes11010099

Nigam, M., Punia, B., Dimri, D. B., Mishra, A. P., Radu, A.-F., & Bungau, G. (2025). Reactive Oxygen Species: A Double-Edged Sword in the Modulation of Cancer Signaling Pathway Dynamics. Cells, 14(15), 1207. https://doi.org/10.3390/cells14151207

Nordengen, A. L., Zheng, C., Krutto, A., Kværner, A. S., Alavi, D. T., Henriksen, H. B., Henriksen, C., Smeland, S., Bøhn, S. K., Paur, I., Shaposhnikov, S., Collins, A. R., & Blomhoff, R. (2024). Effect of a personalized intensive dietary intervention on base excision repair (BER) in colorectal cancer patients: Results from a randomized controlled trial. Free Radical Biology and Medicine, 218, 178–189. https://doi.org/10.1016/j.freeradbiomed.2024.04.211

Paduraru, D. N., Palcau, A. C., Dinca, V. G., Ciuc, D. M., & Constantinescu, A. (2025). The Role of Gut Microbiota in Colorectal Cancer Pathogenesis: A Comprehensive Literature Review. International Journal of Molecular Sciences, 26(24), 11870. https://doi.org/10.3390/ijms262411870

Pan, H.-Y., & Valapala, M. (2022). Regulation of Autophagy by the Glycogen Synthase Kinase-3 (GSK-3) Signaling Pathway. International Journal of Molecular Sciences, 23(3), 1709. https://doi.org/10.3390/ijms23031709

Poillet-Perez, L., & White, E. (2019). Role of tumor and host autophagy in cancer metabolism. Genes & Development, 33(11–12), 610–619. https://doi.org/10.1101/gad.325514.119

Prime, S. S., Darski, P., Hunter, K. D., Cirillo, N., & Parkinson, E. K. (2024). A Review of the Repair of DNA Double Strand Breaks in the Development of Oral Cancer. International Journal of Molecular Sciences, 25(7), 4092. https://doi.org/10.3390/ijms25074092

Shan, C., Wang, Y., & Wang, Y. (2024). The Crosstalk between Autophagy and Nrf2 Signaling in Cancer: from Biology to Clinical Applications. International Journal of Biological Sciences, 20(15), 6181–6206. https://doi.org/10.7150/ijbs.103187

Vickridge, E., Faraco, C. C. F., & Nepveu, A. (2022). Base excision repair accessory factors in senescence avoidance and resistance to treatments. Cancer Drug Resistance, 5(3), 703–720. https://doi.org/10.20517/cdr.2022.36

Xu, Z., Xu, C., Lu, J., He, C., Wang, X., Zhu, D., Wang, A., Zhang, Z., & Jiang, C. (2024). Cytochrome P450 F3 promotes colorectal cancer via inhibiting NRF2-mediated ferroptosis. Translational Oncology, 48, 102077. https://doi.org/10.1016/j.tranon.2024.102077

Yagishita, Y., Gatbonton-Schwager, T. N., McCallum, M. L., & Kensler, T. W. (2020). Current Landscape of NRF2 Biomarkers in Clinical Trials. Antioxidants, 9(8), 716. https://doi.org/10.3390/antiox9080716

Zhang, Y., Li, H., Lv, L., Lu, K., Li, H., Zhang, W., & Cui, T. (2023). Autophagy: Dual roles and perspective for clinical treatment of colorectal cancer. Biochimie, 206, 49–60. https://doi.org/10.1016/j.biochi.2022.10.004

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Published

2026-08-01

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Vol. 4 No. 3 (2026): International Journal of Psychology and Health Science (July - September 2026)

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Copyright (c) 2026 Welly Hartono Ruslim, Himmi Marsiati, Nunung Ainur Rahmah, Wifanto Saditya Jeo

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