Crosstalk of metabolic cell death pathways in colorectal cancer: implications for precision therapy.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related deaths worldwide, with therapeutic resistance being a critical bottleneck limiting patient outcomes. This necessitates novel intervention strategies beyond classical apoptosis paradigms. Metabolically-regulated cell death (particularly ferroptosis and cuproptosis), by targeting the metabolic vulnerabilities of tumor cells, offers new perspectives for overcoming cancer drug resistance. We provide a comprehensive overview of ferroptosis and cuproptosis in CRC, with a focused discussion on their crosstalk, therapeutic strategies, and translational barriers.

Emerging pathways including disulfidptosis are introduced as future directions, though CRC-specific evidence remains preliminary. Ferroptosis is characterized by GPX4 and FSP1 antioxidant system imbalance and lipid peroxidation accumulation, whereas cuproptosis is driven by FDX1-dependent mitochondrial protein lipoylation aggregation. The two form intricate cross-regulatory networks through key nodes such as SLC7A11 and FDX1: while SLC7A11 exerts a protective role in ferroptosis, it triggers disulfide death under glucose deprivation conditions, demonstrating a therapeutic paradigm of "protection-to-lethality" conversion. Immune cells in the tumor microenvironment and gut microbiota bidirectionally modulate the susceptibility of these cell death pathways.

Current therapeutic strategies primarily focus on inducing ferroptosis and cuproptosis, encompassing natural products (e.g., acevaltrate, chagosendine C) and multifunctional nano-platforms, which have demonstrated synergistic anti-CRC activity and potential for combination immunotherapy in preclinical models.

However, fundamental obstacles remain in clinical translation: the lack of specific biomarkers, the blurred heterogeneity of CRC molecular subtyping (CMS), unclear interaction mechanisms between metastatic tumor metabolic death and anoikis resistance, and the absence of long-term data on copper/iron carriers. This review aims to summarize the regulatory mechanisms and functional interplay of ferroptosis and cuproptosis in CRC, critically analyze their translational bottlenecks, and propose multi-pathway synergistic intervention strategies along with biomarker-driven precision stratification approaches. The goal is to provide a prospective paradigm for translating metabolic cell death theories into clinical CRC treatment through foundational clinical research.