The article discusses the role of damage-associated molecular patterns (DAMPs) in radiation injury and their potential as therapeutic targets. Ionizing radiation exposure can cause acute radiation syndrome (ARS), which includes hematopoietic, gastrointestinal, and neurovascular subtypes. The release of DAMPs, such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), mitochondrial DNA (mtDNA), and exRNA, exacerbates ARS by activating inflammatory responses and contributing to organ damage. The article reviews the mechanisms by which DAMPs are released, including apoptosis, necrosis, pyroptosis, ferroptosis, and exosome secretion. It also explores the potential of targeting DAMPs to mitigate radiation-induced injury, highlighting the use of monoclonal antibodies, peptides, decoy receptors, and small molecules. The authors conclude that DAMPs play a crucial role in worsening radiation injury and that targeting them could be a promising therapeutic strategy.The article discusses the role of damage-associated molecular patterns (DAMPs) in radiation injury and their potential as therapeutic targets. Ionizing radiation exposure can cause acute radiation syndrome (ARS), which includes hematopoietic, gastrointestinal, and neurovascular subtypes. The release of DAMPs, such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), mitochondrial DNA (mtDNA), and exRNA, exacerbates ARS by activating inflammatory responses and contributing to organ damage. The article reviews the mechanisms by which DAMPs are released, including apoptosis, necrosis, pyroptosis, ferroptosis, and exosome secretion. It also explores the potential of targeting DAMPs to mitigate radiation-induced injury, highlighting the use of monoclonal antibodies, peptides, decoy receptors, and small molecules. The authors conclude that DAMPs play a crucial role in worsening radiation injury and that targeting them could be a promising therapeutic strategy.