Functionalized micro-/nanoscale metal-organic frameworks (MOFs) hold significant potential in treating uranium-contaminated water and extracting uranium from seawater, but their application in vivo as decorporation agents for uranium-induced nephrotoxicity is fundamentally restricted by the size-dependent glomerular filtration barrier. Herein, we report a one-pot controllable synthesis of amidoxime MOFs with diameters of sub-2.5 nm. The subnanometer dimension enabled precise renal targeting of the MOFs and delivery to proximal tubules, the primary site of uranium deposition. In uranium internal contamination mouse models, delayed treatment with amidoxime MOFs resulted in an 82.5% reduction in renal uranium accumulation, outperforming all currently reported chelating agents, as well as the clinical drug ZnNa3-DTPA, and thus significantly alleviated uranium-induced nephrotoxicity. This subnanometer-scale engineering approach represents a groundbreaking paradigm for the defense against radionuclide-induced nephrotoxicity.

The tumor microenvironment (TME) plays a crucial role in cancer progression and treatment, particularly in the field of immunotherapy. Composed of diverse cell types and extracellular matrix components, the TME collectively contributes to cancer pathogenesis and resistance to treatment. In recent years, innovative strategies targeting the TME have emerged as promising therapeutic approaches for cancer treatments. This review focuses on the latest advancements in engineered nanomaterials designed to modulate the immune‐suppressive characteristics of the TME, including hypoxia, reactive oxygen species levels, high interstitial fluid pressure, and acidity. By strategically manipulating the TME with nanomaterials, we hold promise for creating a more conducive environment for immune cell activation and destruction of tumor cells, thereby enhancing the efficacy of immunotherapy. The development of these nanomaterials represents a significant leap forward in our battle against cancer by offering a novel approach to overcome challenges posed by immune‐suppressive TME.

PURPOSE:Ionizing radiation (IR) can induce long-term alterations in the hematopoietic and immune systems. This study aimed to investigate the potential of luteolin (with known anti-inflammatory and anti-senescence properties), a natural flavonoid, to mitigate radiation-induced hematopoietic and immune system long-term damage in a mouse model. MATERIALS AND METHODS:C57BL/6 mice were subjected to single whole-body irradiation (WBI) to establish a model of radiation-induced long-term damage, with five mice per group. WBI was performed using a γ-ray irradiator at a dose rate of 0.88 Gy/min, with a total radiation dose of 6 Gy. Four months post-IR, mice were administered luteolin (0.5 mg/kg/day) via oral gavage for two months. Flow cytometry was employed to analyze peripheral blood counts, bone marrow hematopoietic stem/progenitor cells (HSPCs) populations, and immune cell compositions in the thymus, spleen, and mesenteric lymph nodes (MLNs). Senescence-associated β-galactosidase (SA-β-Gal) staining and immunohistochemical analysis of p16 and p21 proteins were performed to assess aging-related changes in the spleen and thymus. RESULTS:WBI significantly reduced white blood cell (WBC) counts and induced myeloid-lymphoid skewing, with increased neutrophils and decreased lymphocytes, while also reducing red blood cell (RBC) counts and hemoglobin (HGB) levels. Luteolin did not alter total WBC counts but partially restored lymphocyte proportions and improved RBC and HGB levels. In bone marrow, WBI disrupted the HSPC compartment, decreasing LSKs and CD34+ LSKs while expanding CD34- LSKs and MEPs; these changes were partially reversed by luteolin. In immune organs, luteolin alleviated radiation-induced senescence in the thymus and spleen, increased B-cell proportions, and reduced macrophage accumulation, with minimal effects on T-cell subsets. CONCLUSIONS:Luteolin partially mitigates radiation-induced long-term injury by attenuating cellular senescence and modulating hematopoietic and immune system alterations. These results suggest that luteolin may represent a potential adjunctive strategy for alleviating long-term hematopoietic and immune damage following radiation exposure.

Sensory neurons act as crucial hubs for host defense, tumor immunity, and tissue homeostasis by detecting environmental cues and fine-tuning immune responses. Across a diversity of tissues, these neurons establish specialized neuroimmune units with resident immune cells, translating local stimuli into coordinated physiological adaptations. Central to this crosstalk is calcitonin gene-related peptide (CGRP). Released by activated sensory neurons, CGRP dynamically governs immune cell function, neurogenic inflammation, and tissue repair. This review synthesizes current evidence establishing CGRP as a master regulator of neuroimmune communication. We dissect its highly context-dependent roles in microbial infections, the tumor microenvironment, and barrier tissues, emphasizing how microbial identity, spatial niches, and concurrent signaling cues dictate its functional outcomes. Mechanistically, we explore the molecular cascades through which diverse cell types decode CGRP signals, focusing on receptor subtype selectivity and cell-specific adaptor switching. Furthermore, we evaluate emerging therapeutic strategies targeting the CGRP axis—ranging from small-molecule modulators to monoclonal antibodies—and their transformative potential for treating immune-mediated conditions, from chronic inflammation to malignancies. Ultimately, we identify critical knowledge gaps, such as the “CGRP receptor code” and neuromicrobial feedback loops, which must be resolved to fully harness the therapeutic promise of this neuroimmune axis.

Organismal health is dictated by the interplay between host genetics, microbiota, and environmental stressors like ionizing radiation (IR). However, the role of potential metabolic factors, such as Glycine N-methyltransferase (Gnmt), in coordinating this stress response remains largely unexplored. We aimed to investigate whether a candidate host factor, Gnmt, contributes to the radioprotective effects of Limosilactobacillus reuteri (L. reuteri) and to elucidate their coordination in mitigating IR damage. Label-free proteomics identified IR-responsive proteins. Gnmt function was interrogated using genetic manipulation to assess its impact on apoptosis, triacylglycerol (TAG) and free fatty acid (FFA) utilization, and lifespan. Radioprotective effects of two L. reuteri strains (DSM 17938 and ATCC PTA-6475) were evaluated in wild-type and gnmt mutant flies, with microbiota changes analyzed by 16 S rRNA sequencing. Proteomics identified Gnmt as a potential regulator of IR-induced apoptosis and lipid mobilization. Gnmt overexpression extended post-IR lifespan in both sexes. L. reuteri supplementation suppressed IR-induced apoptosis through a pathway that appears Gnmt-independent. However, while strain DSM 17,938 extended lifespan regardless of Gnmt, strain ATCC PTA-6475 required host Gnmt for radioprotection in males. Beta-diversity analysis demonstrated that L. reuteri moved microbial community structures more closely to non-irradiated controls. This involved suppressing potentially opportunistic Enterobacter and promoting commensal Lactobacillus, effects that were largely contingent upon host Gnmt. L. reuteri supplementation improves survival and suppresses apoptosis in irradiated flies. While cellular protection appears Gnmt-independent, systemic microbiota restoration is associated with host Gnmt function. This suggests a dual-track protective mechanism involving both host-Gnmt-coordinated microbiota remodeling and parallel cellular protection pathways.

With advancements in radiotherapy technologies, the detrimental effects of ionizing radiation on biological systems, particularly the hematopoietic system, have caused significant concern. N6-methyladenosine (m6A), the most pervasive representative of post-transcriptional modifications, plays critical roles in diverse biological events. Non-coding RNA comprises the vast majority of the human genome. This study aimed to explore the role of long non-coding RNA (lncRNA) m6A modification in γ-ray irradiation-induced hematopoietic injury. By using mouse models, it was found that γ-radiation rapidly damaged hematopoietic bone marrow cells (BMCs), triggering apoptosis, oxidative stress and DNA damage, along with up-regulation of m6A Reader proteins. We revealed the time-conditioned landscape of lncRNA m6A methylome of BMCs in the short term after radiation and found that a dynamic "change-then-recover" trend involved. LncRNA Snhg15 was identified as a key regulator through integration analysis of the methylome and transcriptome data. Its m6A modification was closely related to progression of radiation injury in BMCs. Further research demonstrated that the novel m6A Reader LRPPRC could interact with the modification site of Snhg15, stabilize Snhg15 and promote its expression, thereby exacerbating radiation-induced injury to BMCs both in vitro and in vivo. Knockdown of Lrpprc or Snhg15 could alleviate the radiation injury to the hematopoietic system. Additionally, the LRPPRC-Snhg15 axis was involved in the radio-protective efficacy of gut microbiota-derived valeric acid. These findings uncover a novel mechanism by which m6A-modified lncRNA Snhg15 is stabilized by LRPPRC modulates γ-irradiation-induced hematopoietic injury, providing potential therapeutic targets for the prevention and treatment of radiation injuries.

Radiation enteritis, affecting over 90% of pelvic/abdominal radiotherapy patients, is primarily caused by radiation-induced reactive oxygen and nitrogen species (RONS). Active hydrogens, with broad-spectrum RONS scavenging ability, show radioprotective potential but face delivery challenges due to the intestinal mucus barrier and short lifespan. Here, we show drinkable, self-thermophoretic sodium alginate/chitosan oligosaccharide-coated hydrogenated molybdenum oxide nanomachines (HxMoO3@SA@COSs) that exhibit near-infrared (NIR)-driven directional motility and sustained active hydrogen release. In a male mouse model of radiation enteritis, HxMoO3@SA@COSs overcome the mucus barrier, prolong intestinal retention, and deliver active hydrogen to injury sites, enabling precise enteritis therapy. Beyond RONS scavenging, the released hydrogen induces anti-inflammatory macrophage polarization, increases goblet cell abundance, and modulates gut microbiota, promoting intestinal repair. This hydrogen-based, drug-free strategy demonstrates superior efficacy in treating radiation enteritis.

Radiation-induced intestinal injury is a common complication of abdominopelvic cancer radiotherapy, often associated with gut bacteriome dysbiosis. However, the involvement of gut virome in this process remains largely underexplored. Here, it was found that radiation disrupted the gut virome, altered the distribution of phages and their bacterial host. Fecal virome transplantation (FVT) from healthy donors ameliorated radiation-induced intestinal damage and promoted stem cell proliferation by enriching phages targeting Salmonella. Conversely, decreased virome load exacerbated intestinal damage, reduced proliferating stem cells, and impaired secretory lineage differentiation. Mechanistically, exacerbated intestinal injury was associated with hyperactivation of RIG-I and Notch signaling in intestinal stem cells, which was absent in RIG-I-deficient mice. Organoids from RIG-I-deficient mice displayed decreased Notch signals and increased regenerative capacity post radiation. These findings shed light on the intricate interplay between gut virome, intestinal injury, and stem cell responses, highlighting potential therapeutic interventions for targeting the virome to mitigate radiation-induced intestinal damage.

Accidental internal or external exposure to gamma radiation can cause severe injury to the human body. The identification of an effective medication target has become particularly important for the treatment of radiation-induced injury. In this work, Caenorhabditis elegans was found to tolerate high-dose radiation when exposed to an extremely low-temperature environment (at 4 °C) for 4 h before irradiation. Experimental confirmation revealed that metabolites excreted by C. elegans targeted the guanylyl cyclase GCY-5. Furthermore, GCY-5 activation by the excreted metabolites both suppressed lysosome acidification and promoted lipid translocation in lysosomes via FAT-5/SCD5. This ultimately resulted in the mitigation of radiation-induced damage. The pathway discovered in C. elegans was also confirmed in 293T cells, indicating a potential new target for radiation-induced damage research. A radiotherapy prognosis analysis based on the TCGA database indicated that assessing SCD5 expression in patients with kidney renal clear cell carcinoma (KIRC) during clinical treatment may aid in evaluating their suitability for radiotherapy. This study provides clinicians with a valuable basis for developing more effective therapeutic strategies and an experimental basis for future investigations in this area.

The biological damage caused by ionizing radiation (IR) depends not only on the time and doses of exposure to tissue components but also on the developmental state of the cells. Currently, amifostine is the only radiation-protective agent used for clinical indications related to radiation therapy, but this compound has multiple drawbacks including high toxicity, short half-life and no protective effect on the nervous system. Ursolic acid (UA), a natural pentacyclic triterpenoid that exhibits multiple protective effects including anti-inflammatory, anticarcinogenic, and antioxidant effects. Due to its poor solubility and bioavailability, UA is mostly administered with liposomes. In this study we investigated the impact of UA312, an optimized derivative of UA, on radiation-induced developmental toxicity in zebrafish embryos and larvae. Embryo and larvae survival were observed at 4, 24, 48, and 72 hpf. UA312 was administered at 3 hpf, while embryos were irradiated with 6 Gy of γ-irradiation (dose rate: 0.88 Gy/min) at 4 hpf, then the embryos were moved to a fresh buffer. We determined that 40 µM of UA312 was a safe concentration for zebrafish embryos and larvae. We found that treatment with UA312 (40 µM) restored IR-induced early developmental dysplasia of the zebrafish embryos and larvae. Transcriptomic analysis revealed that exposure to IR inhibited multiple pathways related to neurodevelopment and cardiomyocyte function in zebrafish, which were validated by assessing abnormal cardiac morphology, variations in neurotransmitter levels and alterations in locomotor behavior; and that UA312 treatment ameliorated these alterations. We demonstrated that UA312 treatment significantly reversed the related signaling pathways by targeting chrna3 and grik5. In conclusion, this study identified a promising radioprotective drug, UA312, which alleviates IR-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish by targeting chrna3 and grik5. UA312 may be developed as a novel radioprotective agent against acute IR damage in humans.

Introduction Radiation enteritis is one of the most frequent clinical complications of radiotherapy (RT), yet few effective strategies currently exist to protect against that. Anoctamin 1 (ANO1) functions both as a chloride channel and a signal transduction protein, influencing numerous pathophysiological processes. Objectives This study aimed to investigate whether targeting ANO1 could mitigate radiation-induced enteritis while enhancing tumor radiosensitivity. Methods Quantitative PCR (qPCR) and Western blot (WB) were used to assess ANO1 expression and its changes after irradiation. Survival rates were recorded to evaluate the effects of ANO1 agonist and inhibitors. A cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor was administered to irradiated mice to investigate the role of chloride channel in radiation protection. qPCR and WB were executed to analyze the expression of relevant ion channels in intestinal epithelium. Functional validation was conducted using inhibitors in mice and 3D organoids. Fluorescent probe kits detected intracellular ion levels and membrane potential, and WB was performed to elucidate the underlying mechanisms. Finally, the radiosensitizing effect of CaCCinh-A01 was assessed in colorectal cancer (CRC) cells and validated in in vivo models. Results Blocking the calcium-activated chloride channel (CaCC) protein ANO1, which is highly expressed in the colon, protects the intestine from radiation-induced damage. The ANO1 inhibitor CaCCinh-A01, suppresses CaCC currents, downregulates ANO1 protein expression, alleviates radiation-induced intestine injury, and enhances the radiosensitivity of CRC. Mechanistically, CaCCinh-A01 upregulates Na-K-Cl Cotransporter 1 (NKCC1) protein expression, leading to an increase in intracellular Cl- concentration and the inhibition of membrane depolarization in MODE-K cells. This subsequently inhibits p53-mediate DNA damage signaling, ultimately alleviating ionizing radiation-induced intestinal injury. Conclusion These findings suggest that targeting ANO1 not only alleviates radiation-induced intestinal injury in mice but also enhances CRC radiosensitivity. Thus, ANO1 represents a promising therapeutic target for mitigating the side effects of RT in CRC patients.

Glioblastoma (GBM) radiotherapy is hampered by intrinsic radioresistance. Current radiosensitizers face two unresolved hurdles: inability to dynamically traverse sequential physiological barriers of GBM and lack of multitargeted action against the pathways driving radioresistance. Here, we developed h-Pep-MTZ, a biobarrier-adaptive peptide-radiosensitizer addressing both. This system undergoes smart multistage transformations to overcome key delivery barriers: It first circulates as large, negatively charged nanoparticles to prolong plasma half-life; then converts to small, positively charged particles via tumor-overexpressed heparanase for deep tumor penetration; and finally assembles into long nanofibers triggered by lysosomal cathepsin B and acidity to extend tumor retention. Importantly, the nanofibers mechanically disrupt lysosomes, increasing lysosomal membrane permeability, inhibiting AKT activation, reducing autophagy, and impairing cytoskeletal integrity─synergistically sensitizing tumors to radiation. This strategy combined with 6 Gy radiation achieved 82.5% tumor suppression in conventional U251 models and 60.4% in radioresistant U87 models, significantly outperforming the clinical radiosensitizer sodium glycididazole. This strategy provides a paradigm for overcoming GBM radioresistance by leveraging bioresponsive nanoscale transformations and lysosomal targeting.

The widespread application of ionizing radiation (IR) in medicine, while beneficial, also poses potential risks that necessitate effective countermeasures. Both 2-(3-aminopropylamino) ethanethiol (WR-1065) and curcumin are recognized as radioprotective agents; however, their clinical utility is hindered by notable shortcomings that could be addressed through reactive oxygen species (ROS)-responsive amphiphilic nanomaterials. We introduced a newly synthesized poly (ethylene glycol) (PEG)-polycaprolactone (PCL) polymer integrated with diselenide bonds and curcumin (HOOC-SeSe-Cur-PEG-SeSe-Cur-PCL, PEG-Cur-SeSe-PCL). The resulting spherical nanoparticles (NPs), which self-assembled from this polymer, were uniform with an average diameter of 118 nm. As a carrier for WR-1065, these NPs demonstrated a loading capacity of 30.9% and an efficacy of 56.7%. Importantly, the degradation of WR-1065 within the NPs was minimal in gastric fluid, decreasing by only approximately 20% over a 6-hour period. The innovative aspect of these NPs is their design to destabilize in ROS-rich environments, facilitating the release of WR-1065 and curcumin. Indeed, the survival rate of mice increased to 50% when these NPs were orally administered prior to exposure to a lethal dose of whole-body irradiation (8 Gy). The radioprotective impact of WR-1065-loaded NPs was evident in the small intestine of irradiated mice, characterized by the amelioration of radiation-induced epithelial damage, reduction of DNA damage, and inhibition of the apoptotic pathway. Collectively, this oral nanocarrier system for WR-1065 and curcumin holds promise as a potential candidate for the prophylaxis and treatment of acute intestinal injuries induced by IR.

Radiation-induced brain injury (RIBI) represents a severe complication of cranial radiotherapy, substantially diminishing patients’ quality of life. Unlike conventional brain injuries, RIBI evokes a unique chronic neuroinflammatory response that notably aggravates neurodegenerative processes. Despite significant progress in understanding the molecular mechanisms related to neuroinflammation, the specific and precise mechanisms that regulate neuroinflammation in RIBI and its associated toxicological effects remain largely unclear. Additionally, targeted neuroprotective strategies for RIBI are currently lacking. In this study, we systematically characterized the pathophysiology of RIBI using zebrafish (larvae/adults) and murine models. We established direct associations between neuronal damage and cognitive-behavioral deficits. Mechanistically, we proposed a ROS-mitochondrial-immune axis. Specifically, radiation-induced ROS lead to mitochondrial dysfunction, resulting in the leakage of mitochondrial DNA into the cytosol. This, in turn, activated the cGAS-STING pathway, thereby driving persistent microglia-mediated neuroinflammation. Furthermore, we engineered a dual-function nanotherapeutic agent, Pep-Cu5.4O@H151. This agent integrates ultrasmall copper-based nanozymes (Cu5.4O) for ROS scavenging and H151 (a STING inhibitor) and is conjugated with peptides that can penetrate the blood-brain barrier and target microglia. This nanoplatform exhibited excellent synergistic therapeutic efficacy by simultaneously neutralizing oxidative stress and blocking inflammatory cascades. Our research provided an in-depth analysis of radiation-induced neurotoxicity, clarifying the crucial ROS-mitochondrial-immune axis. Moreover, we have developed a precise therapeutic strategy on the basis of this mechanism.

Viruses are widely present in nature and can infect eukaryotic cells, producing a variety of biological effects. Several viruses are capable of coexisting with human cells over the long term, and it has been proven that these viruses possess carcinogenic properties. Radiation therapy is a common method used for treating tumors. Under the influence of radiation, infected tumor cells and uninfected tumor cells exhibit different pathological characteristics and treatment outcomes. Herein, in this chapter, we discuss the impact of five viruses on tumor radiation therapy, including coronavirus disease-2019 (COVID-19), hepatitis B virus (HBV), human papillomavirus (HPV), monkeypox virus, and avian influenza virus. We hope that by summarizing the relationship between viral replication and tumor radiation therapy, we can provide novel insight for future treatments.

The diverse radiation types in medical treatments and the natural environment elicit complex biological effects on both cancerous and non-cancerous tissues. Radiation therapy (RT) induces oncological responses, from molecular to phenotypic alterations, while simultaneously exerting toxic effects on healthy tissue. N6-methyladenosine (m6A), a prevalent modification on coding and non-coding RNAs, is a key epigenetic mark established by a set of evolutionarily conserved enzymes. The interplay between m6A modification and radiobiology of cancerous and non-cancerous tissues merits in-depth investigation. This review summarizes the roles of m6A in the biological effects induced by ionizing radiation and ultraviolet (UV) radiation. It begins with an overview of m6A modification and its detection methods, followed by a detailed examination of how m6A dynamically regulates the sensitivity of cancerous tissues to RT, the injury response in non-cancerous tissues, and the toxicological effects of UV exposure. Notably, this review underscores the importance of novel regulatory mechanisms of m6A and their potential clinical applications in identifying epigenetically modulated radiation-associated biomarkers for cancer therapy and estimation of radiation dosages. In conclusion, enzyme-mediated m6A-modification triggers alterations in target gene expression by affecting the metabolism of the modified RNAs, thus modulating progression and radiosensitivity in cancerous tissues, as well as radiation effects on normal tissues. Several promising avenues for future research are further discussed. This review highlights the importance of m6A modification in the context of radiation biology. Targeting epi-transcriptomic molecules might potentially provide a novel strategy for enhancing the radiosensitivity of cancerous tissues and mitigating radiation-induced injury to normal tissues.

Ionizing radiation (IR) poses a significant threat to both the natural environment and biological health. Exposure to specific doses of ionizing radiation early in an organism's development can lead to developmental toxicity, particularly neurotoxicity. Through experimentation with Xenopus laevis (X. laevis), we examined the effects of radiation on early developmental stage. Our findings revealed that radiation led to developmental abnormalities and mortality in X. laevis embryos in a dose-dependent manner, disrupting redox homeostasis and inducing cell apoptosis. Additionally, radiation caused neurotoxic effects, resulting in abnormal behavior and neuron damage in the embryos. Further investigation into the underlying mechanisms of radiation-induced neurotoxicity indicated the potential involvement of the neuroactive ligand-receptor interaction pathway, which was supported by RNA-Seq analysis. Validation of gene expression associated with this pathway and analysis of neurotransmitter levels confirmed our hypothesis. In addition, we further validated the important role of this signaling pathway in radiation-induced neurotoxicity through edaravone rescue experiments. This research establishes a valuable model for radiation damage studying and provides some insight into radiation-induced neurotoxicity mechanisms.

Targeted therapy targets the driver genes of tumor cells and effective inhibitors were developed to treat tumors by inhibiting tumor cell proliferation, interfering with the cell cycle, inducing tumor cell apoptosis, and inhibiting tumor angiogenesis. The emergence of RNA therapeutics provides more opportunities to target some driver genes which cannot be targeted with conventional drugs. However, the response of these targeted drugs in patients may be limited by their potential drug toxicity and tolerance. With the development of positron emission tomography (PET) and molecular biology, a number of passenger genes that do not have a driving role in tumor growth such as prostate-specific membrane antigen (PSMA) in prostate cancer, have been developed for widespread use in the diagnosis and treatment of cancer through radiolabeled molecular tracers. Radiopharmaceutical targets exhibit high specificity, which contributes to enhancing inhibitory activity in tumor but avoiding toxic effects on normal tissues. In addition, these radiopharmaceuticals have been continuously upgraded through chemical structure optimization such as regulating linkage lengths, hydrophobicity and charge, introducing albumin-binding entities and increasing the amphiphilicity of tracers enables radiopharmaceuticals to traverse cell and nuclear membranes, which have further improved diagnostic sensitivity/therapeutic specificity and reduced off-target toxicity.

The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT) potentiates the tumoricidal effects of radiation and degrades the intertwined adverse events in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. FMT cumulates Roseburia intestinalis (R. intestinalis) in the gastrointestinal tract. Oral gavage of R. intestinalis assembles at the CRC site and synthetizes butyrate, sensitizing CRC to radiation and alleviating intestinal toxicity in primary and CRC hepatic metastasis mouse models. R. intestinalis-derived butyrate activates OR51E1, a G-protein-coupled receptor overexpressing in patients with rectal cancer, facilitating radiogenic autophagy in CRC cells. OR51E1 shows a positive correlation with RALB in clinical rectal cancer tissues and CRC mouse model. Blockage of OR51E1/RALB signaling restrains butyrate-elicited autophagy in irradiated CRC cells. Our findings highlight that the gut commensal bacteria R. intestinalis motivates radiation-induced autophagy to accelerate CRC cell death through the butyrate/OR51E1/RALB axis and provide a promising radiosensitizer for CRC in a pre-clinical setting.