Article Impact Level: HIGH Data Quality: STRONG Summary of Cellular and Molecular Gastroenterology and Hepatology https://doi.org/10.1016/j.jcmgh.2025.101607 Dr. Xiangsheng Zuo et al.
Points
- Colorectal 15-Lipoxygenase-1 (ALOX15) expression is essential for omega-3 fatty acids to suppress tumor growth.
- EPA and DHA consistently inhibited colorectal tumor formation in mice expressing human ALOX15.
- This antitumorigenic effect was linked to increased resolvin production and reduced inflammation.
- Resolvins generated by ALOX15 suppressed inflammatory cytokines and promoted macrophage phagocytosis in vitro.
- ALOX15 status should be considered when designing colon cancer prevention strategies using omega-3s.
Summary
This research investigated the role of colorectal 15-Lipoxygenase-1 (ALOX15) as a critical host factor determining the efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in colorectal tumorigenesis (CRT). Previous studies on omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and CRT have yielded conflicting results, with ALOX15, an enzyme crucial for resolvin production from EPA and DHA, frequently lost in human colorectal cancer. This study hypothesized that ALOX15 expression in the colon mediates the effects of EPA and DHA on resolvin generation and subsequent tumor formation.
Using multiple mouse models engineered to express human ALOX15 in colonic epithelial cells, the effects of EPA and DHA supplementation were rigorously evaluated. In control mice lacking transgenic human ALOX15, dietary EPA and DHA resulted in minimal changes in resolvin production and exhibited variable effects on CRT. Conversely, mice expressing human ALOX15 consistently demonstrated significant inhibition of colorectal tumor formation when supplemented with EPA and DHA. These antitumorigenic effects were accompanied by a robust increase in resolvin production, a reduction in colonic expression of pro-inflammatory chemokines and cytokines such as CCL2, IL-1β, and IL-6, a decrease in tumor-associated macrophages, and enhanced infiltration of CD8α+ T cells within the tumor microenvironment.
In vitro experiments further supported these findings, showing that resolvin E1 (RvE1) and resolvin D5 (RvD5), the primary resolvins generated by ALOX15, effectively suppressed CCL2, IL-1β, and IL-6 production and promoted phagocytic activity in murine macrophages. The study concludes that colonic ALOX15 expression is indispensable for EPA and DHA to effectively generate resolvins and consistently suppress CRT. Therefore, the ALOX15 expression status in the colon should be considered when developing ω-3 PUFA-based prevention strategies for colon cancer.
Link to the article: https://www.cmghjournal.org/article/S2352-345X(25)00148-1/fulltext
References
Zuo, X., Kiyasu, Y., Liu, Y., Deguchi, Y., Liu, F., Moussalli, M., Tan, L., Wei, B., Wei, D., Yang, P., & Shureiqi, I. (2025). Colorectal 15-lipoxygenase-1 as a host factor determining the effects of eicosapentaenoic acid and docosahexaenoic acid on colorectal tumorigenesis in mice. Cellular and Molecular Gastroenterology and Hepatology, 101607. https://doi.org/10.1016/j.jcmgh.2025.101607
