Damage-associated molecular pattern (DAMP) (DAMP)

Damage-associated molecular patterns (DAMPs), also known as alarmins, are endogenous molecules that perform essential physiological functions within various cellular compartments but are released into the extracellular environment upon cell stress, injury, or non-programmed death [1, 10]. Once extracellular, DAMPs function as potent ligands for pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE), thereby initiating innate immune responses and sterile inflammation [1, 2]. Major examples include High Mobility Group Box 1 (HMGB1), S100 proteins, and extracellular ATP, each playing distinct roles in coordinating tissue repair or driving pathological inflammation in diseases such as sepsis, myocardial infarction, and rheumatoid arthritis [3, 11]. In oncology, the induction of DAMP release is the defining feature of immunogenic cell death (ICD), which is leveraged by certain chemotherapies to stimulate an anti-tumor T-cell response [15, 16]. Conversely, drug development for inflammatory conditions focuses on neutralizing these alarmins or blocking their cognate receptors to prevent chronic tissue damage [13, 14]. While targeting DAMPs offers significant therapeutic potential, challenges remain regarding the risk of impairing normal wound healing and the potential for broad immunosuppression [3, 12].

Other names

AlarminEndogenous danger signalDanger-associated molecular patternDanger signalCell-death associated molecular pattern

Therapeutic strategies target the DAMP signaling axis through the direct neutralization of extracellular alarmins using monoclonal antibodies or decoy receptors, the pharmacological antagonism of pattern recognition receptors (PRRs) such as TLR4, RAGE, and P2X7, and the active inhibition of DAMP secretion or passive release pathways from stressed or dying cells.