Colorectal cancer (CRC) is a prevalent and aggressive tumor. Globally, CRC is the third most diagnosed cancer and a leading cause of cancer-related mortality. However, its fatality rank varies significantly by regions: in the United States, CRC is the third deadliest cancer, while in China, it ranks the fifth (Siegel et al., 2024). Liver metastasis, occurring in 20–25 % of CRC cases, is a major contributor to poor prognosis, with metastatic CRC (mCRC) exhibiting a 5-year survival rate below 15 % despite multimodal therapies (Zhang et al., 2022, Zhou et al., 2021). Current treatment strategies for mCRC integrate surgery, chemotherapy, and targeted agents (e.g., anti-EGFR/anti-VEGF therapies), yet intrinsic and acquired resistance remain pervasive challenges (Shin et al., 2023). Therefore, further investigation is required into synthetic treatment strategies for mCRC. While stereotactic body radiation therapy (SBRT) offers localized control for unresectable hepatic metastases, intrinsic and acquired resistance mechanisms limit its efficacy. Emerging evidence highlights the role of tumor microenvironment remodeling, DNA repair pathways (e.g., ATM/ATR activation), and antioxidant defense systems (e.g., glutathione synthesis) in mediating SBRT resistance (Moul, 2024, Peng et al., 2023). During the process of clinical treatment, we have seen that the responsiveness to SBRT differs among patients with CRC that has progressed to liver metastasis (McDermott et al., 2023). Despite advances in combinatorial therapies, a subset of patients exhibits persistent resistance, underscoring the need for novel molecular targets.

CRC liver metastasis represents a therapeutic challenge due to intrinsic resistance to conventional therapies, including SBRT. While SBRT induces lethal oxidative stress, tumors often evade cell death by activating antioxidant and pro-survival pathways. Central to this adaptation is nuclear factor erythroid 2-related factor 2 (NRF2), a master transcriptional regulator of redox homeostasis. In CRC, NRF2 overexpression correlates with poor prognosis and therapy resistance, driven by its ability to upregulate detoxification enzymes and suppress ferroptosis—a lipid peroxidation-dependent cell death process. (Dodson et al., 2019, Guan et al., 2023). Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has recently emerged as a promising therapeutic target in radiation-resistant cancers. Unlike apoptosis, ferroptosis bypasses classical death pathways, offering a complementary approach to overcome therapy resistance (Lei et al., 2021). In CRC, dysregulation of ferroptosis regulators—notably the cystine/glutamate antiporter SLC7A11 (xCT)—correlates with poor treatment outcomes (Wang et al., 2023). Ferroptosis evasion is further mediated by SLC7A11 (xCT), a cystine/glutamate antiporter that sustains glutathione (GSH) synthesis. By importing cystine for GSH production, SLC7A11 enables glutathione peroxidase 4 (GPX4) to neutralize lipid peroxides, thereby shielding tumors from radiation-induced ferroptosis (Dixon et al., 2012, Koppula et al., 2021). Notably, SLC7A11 expression is transcriptionally regulated by NRF2, whose activity is modulated by upstream stress-responsive kinases. Among these kinases, the c-Jun N-terminal kinase (JNK)/c-Jun axis emerges as a critical mediator of therapy resistance. Activated by DNA damage or oxidative stress, JNK phosphorylates c-Jun, enhancing its ability to drive pro-survival gene expression, including NRF2. This creates a feedforward loop where JNK/c-Jun activation amplifies NRF2-dependent antioxidant programs, perpetuating SLC7A11-mediated ferroptosis resistance (Dhanasekaran and Reddy, 2008, Rojo et al., 2014). Despite these insights, the hierarchical integration of JNK/c-Jun, NRF2, and SLC7A11 into a cohesive resistance axis remains unexplored.

Radiation therapy (RT) employs ionizing radiation to eliminate tumors by inducing an excessive accumulation of reactive oxygen species (ROS) within tumor cells and depleting the antioxidant GSH. This leads to accumulation of iron ions, ultimately triggering a unique form of cell death, known as ferroptosis (Lei et al., 2021). Iron metabolism is crucial for maintaining normal physiological processes (Galaris et al., 2019). Therefore, a combination of ionizing radiation and ferroptosis inducers (FINs) is a potential therapeutic strategy for overcoming radiotherapy resistance in cancer (Zheng and Conrad, 2020). FIN + RT combination therapies have been reported to be safe in pre-clinical studies (Lei et al., 2021). Sorafenib has been shown to induce ferroptosis by targeting SLC7A11, a key subunit of the system Xc⁻. By inhibiting SLC7A11, sorafenib reduces cystine uptake and limits GSH synthesis. The depletion of GSH subsequently impairs the activity of GPX4. As GPX4 activity declines, the accumulation of lipid peroxides reaches toxic levels, triggering ferroptosis (Zhang et al., 2025). Sorafenib also exerts its ferroptosis-inducing effects by interacting with iron metabolism pathways. It increases intracellular levels of free iron, partly by inhibiting ferritin stability. The elevated iron levels promote the Fenton reaction. Research has shown that combining sorafenib with iron supplementation or other agents that modulate iron homeostasis can enhance its therapeutic efficacy, offering new avenues for CRC treatment (Zheng et al., 2024). However, clinical trials are required to confirm the efficacy and safety of these treatment strategies.

Here, we seek to explore the possibility of combining ferroptosis inducers to enhance the efficacy of SBRT for mCRC patients with liver metastases. Our study showed that the expression of SLC7A11 was a key factor in the resistance to radiation therapy in mCRC, and SBRT in combination with a SLC7A11-targeting approach promoted ferroptosis and inhibited tumor growth. We proposed a novel therapeutic strategy involving the combination of SBRT with sorafenib, which inhibits SLC7A11, for the treatment of patients with mCRC and conducted a single arm phase II clinical that provided encouraging results.