Study on the Role and Related Mechanism of ALDH1B1 in the Development of Colorectal Cancer

Aldehyde dehydrogenases (ALDHs) comprise a broad superfamily of metabolic enzymes, with 19 gene groups identified in the human genome. These genes participate in diverse biological processes, including the detoxification of exogenous and endogenous aldehydes. In recent years, ALDHs have garnered increasing attention due to their association with stem cell-related characteristics in a wide range of hematopoietic malignancies and solid tumors. ALDH1B1, an isoform and member of the ALDH superfamily, is aberrantly expressed in multiple cancers. For instance, ALDH1B1 is dysregulated in pancreatic cancer (particularly pancreatic ductal adenocarcinoma, PDAC), where it drives tumor progression through multiple mechanisms: maintaining stemness (e.g., activating Notch and Wnt/β-catenin pathways), metabolic reprogramming (acetaldehyde metabolism, reducing toxic aldehyde accumulation while generating NADPH to sustain redox balance), activating oncogenic pathways (e.g., inducing WNT signaling to promote epithelial-mesenchymal transition and enhance invasiveness), and conferring therapy resistance. ALDH1B1 overexpression induces significant changes in cell morphology, proliferation rates, and clonogenic efficiency, thereby contributing to lung adenocarcinoma development. In esophageal carcinogenesis, three genome-wide significant loci in heterozygotes include ALDH1B1, which exhibits a genome-wide significant interaction with rs671, potentially increasing the risk of esophageal cancer (a classic alcohol-associated disease). Domestic studies have shown that miR-761 can target and suppress ALDH1B1 to inhibit osteosarcoma cell proliferation, migration, and invasion. Furthermore, ALDH1B1 promotes colorectal cancer progression by regulating cancer stemness and key oncogenic signaling pathways. This article elucidates the mechanistic roles of ALDH1B1 in various malignancies, with a particular focus on its specific interactions in the development and progression of colorectal cancer. Notably, ALDH1B1 promotes colorectal carcinogenesis by mediating unique metabolic reprogramming processes. On one hand, ALDH1B1 maintains intracellular redox balance through acetaldehyde oxidation, creating a favorable metabolic microenvironment for cancer stem cells. On the other hand, its involvement in retinoic acid metabolism dysregulation aberrantly activates key oncogenic pathways such as Wnt/β-catenin signaling. Furthermore, ALDH1B1 enhances the glycolytic switch (the Warburg effect) by modulating mitochondrial energy metabolism, thereby supplying the bioenergetic and biosynthetic precursors required for rapid tumor cell proliferation. These metabolic regulatory mechanisms synergize with ALDH1B1’s role in sustaining cancer stem cell properties, collectively forming a multidimensional network through which ALDH1B1 drives colorectal cancer progression. A deeper understanding of the logical relationship between ALDH1B1-mediated metabolic regulation and carcinogenesis will provide a more comprehensive insight into its role in various cancers, particularly colorectal cancer, and offer a theoretical foundation for developing novel ALDH1B1-targeted therapeutic strategies. However, more detailed molecular mechanisms, clinical relevance, and potential therapeutic value require further experimental and clinical validation.