Complement activation beyond the traditional cascades: extracellular to intracellular signaling network

The complement system, as an evolutionarily conserved arm of innate immunity, plays pivotal roles in diverse pathophysiological processes, including homeostasis maintenance, cellular metabolism modulation, and inflammatory regulation. Although traditional activation pathways are well-characterized, growing evidence has revealed noncanonical complement activation mechanisms. These include cross talk with intravascular coagulation, kinin, and fibrinolytic cascades, proteases leaking into the interstitium, hypochlorite or oxygen radicals, and even intracellular activation pathways or membrane-anchored serine proteases, highlighting unprecedented complexity in complement biology. This review comprehensively summarizes the proteases involved in these processes and their potential pathophysiological functions. However, the physiological importance of these pathways requires further investigation, especially regarding whether coagulation, kinin, and fibrinolytic enzymes can functionally activate complement in vivo, and the cell- and context-specific mechanisms that regulate intracellular complement activation, as well as the dynamic integration of traditional and noncanonical complement activation pathways under various challenges. Future investigations should integrate multiomics, super-resolution imaging, and gene editing tools to discriminate physiological regulation from pathological "noise," ultimately advancing precise targeted complement therapeutics.