Structural and molecular principles of DAMP biology.

Damage-associated molecular patterns (DAMPs) are endogenous danger signals. They can be preformed molecules released upon membrane rupture and stress-induced or newly generated factors arising during cell death. These signals link cellular demise to diverse host responses. Rather than passive by-products, DAMPs are actively mobilized through membrane-remodeling proteins, vesicular trafficking and metabolic regulation. Conformational changes, oligomerization and post-translational modifications shape their release and immunogenicity, as illustrated by redox-dependent DAMP states, pore-forming gasdermins and MLKL, and NINJ1-mediated membrane rupture. At the sensing interface, receptors such as TLR4, P2X7 and AGER, together with cytosolic STING1 pathways, translate DAMP recognition into downstream signaling through assembly-driven mechanisms. Cross-talk with metabolic pathways and membrane repair systems, including ESCRT-III and autophagy, further refines DAMP signaling dynamics. Here, we survey and contextualize recent literature to provide a structural and molecular framework for understanding how DAMPs encode immune outcomes and highlight opportunities for targeted therapeutic intervention.