DAMP signaling networks: from receptors to diverse pathophysiological functions

Damage-associated molecular patterns (DAMPs) are endogenous molecules released or exposed during cellular stress, injury, or death. Initially characterized as danger signals that alert the immune system, DAMPs are now recognized as pivotal regulators of innate and adaptive immunity through receptor-mediated signaling mechanisms.

This review aims to elucidate the diverse receptors and intracellular signaling pathways activated by DAMPs and to explore their multifaceted roles in immune modulation, tissue repair, and disease pathogenesis.

DAMP receptors are broadly divided into pattern recognition receptors (PRRs) such as TLRs, NLRs, and RLRs, and non-PRR receptors such as GPCRs, AGER/RAGE, and ion channels. Activation of these receptors initiates downstream signaling cascades including NF-κB, MAPK, and cGAS-STING pathways. DAMP signaling orchestrates a broad range of immunological and cellular processes, including the activation of immune responses, modulation of cell proliferation and migration, promotion of fibrosis and angiogenesis, and the induction of regulated cell death pathways. Dysregulation of DAMP signaling contributes to the pathogenesis of infectious diseases, autoimmune disorders, and cancer, highlighting its potential as a therapeutic target.