Colorectal Cancer (CRC)

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. At the core of CRC’s pathogenesis lie aberrant signaling pathways that drive tumorigenesis, sustain cancer cell proliferation, and enable metastatic dissemination[1]. These pathways, which include the Wnt/β-catenin, RAS/RAF/MEK/ERK, phosphoinositide 3-kinase (PI3K)/AKT, and transforming growth factor-beta (TGF-β) circuits, among others. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression[2].

CRC is driven by the dysregulation of several key signaling pathways that collectively promote the hallmark capabilities acquired during tumorigenesis. These include the Wnt, IGF2, ErbB, TGF-β, Notch, Hedgehog, and TNFα pathways (Figure 1). It details how extracellular signals are transmitted through receptors and intracellular molecules to the nucleus, highlighting the complexity and interconnectivity of these signaling networks in the development and progression of colorectal cancer [2].

E3 ubiquitin ligases play a pivotal role in the initiation and progression of colorectal cancer. While some E3 ligases act as tumor suppressors by promoting the degradation of oncogenes, others function as oncogene activators through either inhibiting the degradation of tumor suppressor genes or disrupting metabolic switch proteins (Figure 2). These enzymes tag substrate proteins with ubiquitin and subsequently degrade key components in signaling pathways. By regulating these ubiquitination and degradation processes, E3 ligases can either act as promoters or inhibitors of tumor development[3].

In addition to E3 ligases, the UPS has also been the target of targeted protein degradation (TPD) therapies in the last two decades [4]. Targeted protein degradation has emerged as a promising approach in the treatment of cancers, including CRC(Figure 3). The intricate interplay between the UPS and the autophagy–lysosomal pathway requires further exploration, and future research should focus on understanding the shared roles of multiple protein degradation pathways in CRC therapy[3].

CRC is more strongly associated with ferroptosis than other cancers. First, due to the special environment of the gastrointestinal tract, TFRC is overexpressed in CRC in colorectal cancer, and second, colorectal cancer is the only malignancy that maintains a source of iron uptake, which leads to the presence of excess iron in cells, and ferroptosis is more likely to occur [5].In addition, the ROS content in CRC cells is usually higher than that in other normal cells. Thus ROS may induce ferroptosis in cancer cells without affecting normal cells(Figure 4).Therefore, understanding the role and regulation mechanism of ferroptosis in CRC plays a crucial role in the treatment of CRC[6].

5. Role of copper and coppertosis in CRC

Recent studies have found higher copper levels in CRC tissues and patient sera (mainly detected by plasma CP levels) than in healthy individuals[7], indicating that copper plays an important role in CRC development and cell proliferation. Elevated copper levels are critical not only for the development of CRC but also for its metastasis, particularly to the liver, which is the most common site of distant CRC metastasis and a storage organ for copper[8]. Recent studies have shown that copper levels in CRC liver metastases are significantly higher than those in normal liver tissues[9]. In summary, copper and copper‐binding proteins are inextricably linked to CRC proliferation and metastasis (Figure 5), making targeting copper ions a promising treatment for CRC[10].

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