Radiation‐induced heart disease (RIHD) is a prevalent cardiovascular complication of radiation therapy, with coronary heart disease being the most common manifestation. Clinical presentations of RIHD vary and may include conduction abnormalities, ischemic heart disease, cardiomyopathy, heart failure, and valvular damage. Even low doses of radiation significantly increase the risk of cardiovascular disease, often associated with severe stenosis detected via angiography. Radiation‐induced damage to the cardiac endothelium triggers inflammatory responses and oxidative stress, which contribute to the progression of atherosclerosis. This study explores how radiation activates multiple signaling pathways through the generation of reactive oxygen species, resulting in vascular endothelial damage, cellular senescence, inflammatory responses, and DNA damage. It further examines the impact of radiation on vascular integrity and tight junction proteins, leading to increased vascular permeability and infiltration by inflammatory cells. From a clinical perspective, we emphasize the challenges posed by the coexistence of tumors in many patients with RIHD, as tumors complicate the microenvironment and may have mutually reinforcing interactions with radiation‐induced damage. We also discuss various therapeutic strategies, including novel approaches targeting cellular senescence and immune responses, with a focus on the potential use of navitoclax and IL‐6 (interleukin‐6) inhibitors to prevent irreversible cardiomyocyte fibrosis and ongoing vascular damage. In conclusion, RIHD is a multifaceted disease involving complex biological processes and signaling pathways. Early intervention and targeted therapies are crucial for improving patient outcomes. Future research should prioritize uncovering the molecular mechanisms of RIHD and developing more effective therapeutic strategies.

Background: Intestinal acute radiation syndrome (IARS) represents a life-threatening component of acute radiation syndrome with limited effective countermeasures. Understanding molecular determinants governing intestinal epithelial resilience to ionizing radiation is critical for developing radiation toxicity mitigation strategies. Objectives: This study investigates the role of PIKfyve, a phosphoinositide kinase essential for endolysosomal homeostasis, in modulating radiation-induced intestinal toxicity. Methods: We utilized an inducible intestinal epithelial-specific PIKfyve-knockout mouse model (PIKfyve cKO) subjected to 10 Gy abdominal irradiation. Intestinal toxicity was assessed through histopathology, barrier permeability (FD4 assay), apoptosis markers, and transcriptomic profiling. Small intestinal organoids were employed for mechanistic validation. Results: PIKfyve deletion alone did not perturb normal gut architecture but precipitated severe post-irradiation toxicity, including villous atrophy, crypt hypoplasia, and massive crypt-cell apoptosis. Barrier dysfunction was evidenced by elevated serum FD4 and heightened systemic pro-inflammatory cytokines, culminating in markedly increased mortality. Transcriptomic analysis revealed potentiated DNA-damage signaling and amplified inflammatory cascades in PIKfyve-deficient intestines. Conclusions: These findings identify PIKfyve as a critical guardian of intestinal epithelial integrity against radiation toxicity. Given emerging PIKfyve inhibitors in cancer therapy, our results raise important safety considerations for clinical radiotherapy and position PIKfyve as a potential target for radiation toxicity mitigation.

Background: Intestinal acute radiation syndrome (IARS) represents a life-threatening component of acute radiation syndrome with limited effective countermeasures. Under-standing molecular determinants governing intestinal epithelial resilience to ionizing ra-diation is critical for developing radiation toxicity mitigation strategies. Objectives: This study investigates the role of PIKfyve, a phosphoinositide kinase essential for endolysosomal homeostasis, in modulating radiation-induced intestinal toxicity. Methods: We utilized an inducible intestinal epithelial-specific PIKfyve-knockout mouse model (PIKfyve cKO) subjected to 10 Gy abdominal irradiation. Intestinal toxicity was as-sessed through histopathology, barrier permeability (FD4 assay), apoptosis markers, and transcriptomic profiling. Small intestinal organoids were employed for mechanistic vali-dation. Results: PIKfyve deletion alone did not perturb normal gut architecture but precipitated severe post-irradiation toxicity, including villous atrophy, crypt hypoplasia, and massive crypt-cell apoptosis. Barrier dysfunction was evidenced by elevated serum FD4 and heightened systemic pro-inflammatory cytokines, culminating in markedly increased mortality. Transcriptomic analysis revealed potentiated DNA-damage signaling and am-plified inflammatory cascades in PIKfyve-deficient intestines. Conclusions: These findings identify PIKfyve as a critical guardian of intestinal epithelial integrity against radiation toxicity. Given emerging PIKfyve inhibitors in cancer therapy, our results raise important safety considerations for clinical radiotherapy and position PIKfyve as a potential target for radiation toxicity mitigation.

Background: Early circulating metabolic indicators of radiation-induced intestinal injury remain to be explored. Methods: Male C57BL/6J mice received 0, 6, 8, 10, 12, or 14 Gy total-body irradiation. The study integrated 30-day survival monitoring, intestinal histological assessment, and targeted plasma metabolomics on days 1, 3, and 7 after irradiation, together with intestinal biochemical measurements and analysis of publicly available single-cell transcriptomic datasets. Results: Mortality increased sharply between 8 and 10 Gy, accompanied by progressive crypt–villus injury. Both plasma and intestinal tissue 5-hydroxylysine levels increased at lower doses but decreased at higher doses. Plasma hydroxyproline and citrulline levels decreased, while intestinal urea was reduced at high doses despite stable plasma urea concentrations. Plasma serotonin increased during the early phase after irradiation. Single-cell analysis provided cellular context for collagen hydroxylation, nitrogen metabolism, and the tryptophan–serotonin metabolic pathway. Conclusions: Circulating amino acids and related metabolites exhibited dose- and time-dependent alterations that were synchronous with the progression of intestinal radiation injury, providing preliminary evidence for further exploration of candidate indicators for early injury assessment.