Radiation‐induced lung injury (RILI) is frequently observed in patients undergoing radiotherapy for thoracic malignancies, constituting a significant complication that hampers the effectiveness and utilization of tumor treatments. Ionizing radiation exerts both direct and indirect detrimental effects on cellular macromolecules, including DNA, RNA and proteins, but the impact of oxidized RNA in RILI remains inadequately explored. Mesenchymal stem cells (MSCs) can repair injured tissues, and the reparative potential and molecular mechanism of MSCs in treating RILI remains incompletely understood. This study aimed to investigate the therapeutic effects and mechanisms of action of three distinct sources of MSCs, including human umbilical cord mesenchymal stem cells (UCMSCs), bone marrow mesenchymal stem cells (BMSCs), and adipose‐derived stem cells (ADSCs), in thoracically irradiated mice. Comparative analysis revealed that all three types of MSCs exhibited the ability to mitigate radiation‐induced inflammatory infiltration, alveolar hemorrhage, and alveolar wall thickening in the lung tissue of the mice. MSCs also attenuated RILI by decreasing inflammatory factors, upregulating anti‐inflammatory factor expression, and reducing collagen accumulation. Immunohistochemical results showed that all three MSCs reduced radiation‐induced cell apoptosis and promoted the regeneration of lung tissue cells. The analysis of malondialdehyde (MDA) and 8‐hydroyguanosine (8‐OHG) content indicated that MSCs possess reparative properties against radiation‐induced oxidative damage in lung tissue. The study provides evidence that UCMSCs are a more appropriate therapeutic option for RILI compared to BMSCs and ADSCs. Additionally, MSCs effectively reduce the accumulation of oxidized RNA in RILI, thereby, presenting a unique avenue for investigating the underlying mechanism of MSC‐based treatment for RILI.

Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-transcriptional modifications. While ionizing radiation (IR) induces cellular damage through direct DNA breaks, reactive oxygen species (ROS)-mediated oxidative stress, and bystander effects, the functional involvement of lncRNAs in the radiation response remains incompletely characterized. Here, through genome-wide CRISPR activation (CRISPRa) screening in non-small cell lung cancer (NSCLC) cells, we identified LOC401312 as a novel radiosensitizing lncRNA, the stable overexpression of which significantly enhanced IR sensitivity. Transcriptomic profiling revealed that LOC401312 transcriptionally upregulates carbamoyl-phosphate synthase 1 (CPS1), a mitochondrial enzyme involved in pyrimidine biosynthesis. Notably, CPS1 overexpression recapitulated the radiosensitization phenotype observed with LOC401312 activation. Mechanistic investigations revealed that CPS1 suppresses the phosphorylation of ATM kinase (Ser1981) protein, which is a key mediator of DNA damage checkpoint activation. This study established the LOC401312–CPS1–ATM axis as a previously unrecognized regulatory network governing radiation sensitivity, highlighting the potential of lncRNA-directed metabolic rewiring to impair DNA repair fidelity. Our findings not only expand the functional landscape of lncRNAs in DNA damage response but also provide a therapeutic rationale for targeting the LOC401312–CPS1 axis to improve radiotherapy efficacy in NSCLC.

Ionizing radiation (IR) induces severe hematopoietic injury by causing DNA and RNA damage as well as activating the immune responses, necessitating the development of effective therapeutic strategies. Ribonuclease L (RNase L) as an innate immune response pathway is triggered by exogenous and endogenous abnormal dsRNA under viral infection and dyshomeostasis, thereby activating the immune responses. Thus, we investigated the effect of RNase L on irradiation-induced bone marrow damage using RNase L knockout (RNase L^−/−) mice. Phenotypic analysis revealed that RNase L knockout mitigates irradiation-induced injury in the bone marrow. Further investigation into the mechanism of RNase L by RNA-seq, qRT-PCR, and CBA analysis demonstrated that RNase L deficiency counteracts the upregulation of genes related to immune responses induced by irradiation, including cytokines and interferon-stimulated genes. Moreover, RNase L deficiency inhibits the increased levels of immunoglobulins in serum induced by irradiation. These findings indicate that RNase L plays a role in the immune response induced by irradiation in the bone marrow. This study further enhances our understanding of the biological functions of RNase L in the immune response induced by irradiation and offers a novel approach for managing irradiation-induced bone marrow injury through the regulation of RNase L activation.

Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-transcriptional modifications. While ionizing radiation (IR) induces cellular damage through direct DNA breaks, reactive oxygen species (ROS)-mediated oxidative stress, and bystander effects, the functional involvement of lncRNAs in radiation response remains incompletely characterized. Here, through genome-wide CRISPR activation (CRISPRa) screening in non-small cell lung cancer (NSCLC) cells, we identified LOC401312 as a novel radiosensitizing lncRNA, the stable overexpression of which significantly enhanced IR sensitivity. Transcriptomic profiling revealed that LOC401312 transcriptionally upregulates carbamoyl-phosphate synthase 1 (CPS1), a mitochondrial enzyme involved in pyrimidine biosynthesis. Notably, CPS1 overexpression recapitulated the radiosensitization phenotype observed with LOC401312 activation. Mechanistic investigations revealed that CPS1 suppresses the phosphorylation of ATM kinase (Ser1981) and XRCC1 protein levels, which are key mediators of DNA damage checkpoint activation and base excision repair, respectively. This study establishes the LOC401312-CPS1-ATM/XRCC1 axis as a previously unrecognized regulatory network governing radiation sensitivity, highlighting the potential of lncRNA-directed metabolic rewiring to impair DNA repair fidelity. Our findings not only expand the functional landscape of lncRNAs in DNA damage response but also provide a therapeutic rationale for targeting the LOC401312-CPS1 axis to improve radiotherapy efficacy in NSCLC.