Fatih Demir, Elina Kovalenko, Moritz Lassé, Esben B. Svenningsen, Jens Magnus Bernth Jensen, A. Billing, Kathrin Groeneveld, Arvid Hutzfeldt, Lars Nilges, João P. L. Guerra, Krzysztof J Pietrzak-Lichwa, Yifan Tan, Elizabeth Colby, Annette G. Hansen, Naziia Kurmasheva, David Olagnier, Dongwoo Choi, M Richter, Sandra D. Laufer, Fabian Braun, Sally Johnson, Marcus Krüger, Tobias B. Huber, Elion Hoxha, Oliver M. Steinmetz, Ralf Mrowka, Simon Melderis, Moin A. Saleem, Thomas B. Poulsen, G.R. Andersen, Steffen Thiel, Anne Troldborg, Markus M. Rinschen
Dysregulated proteolysis is central to autoimmune pathogenesis. The complement cascade, a major protease network, generates fragments that modulate immunity and tissue injury. We developed a scalable blood plasma N-terminomics workflow that markedly expands detection of proteolytic events in vitro and in vivo. Applied to 143 systemic lupus erythematosus (SLE) patients, Multi-Omics Factor Analysis (MOFA) linked N-terminal signatures to immunological and clinical heterogeneity. This revealed a previously unrecognized complement fragment, C3-LHF1, encompassing the C345C domain and rivaling, based on intensity detected by mass spectrometry, the abundance of canonical fragments like C3a and C3b. C3-LHF1 associated with renal function and remission in lupus nephritis, and exhibited dual functions: inhibiting classical and lectin complement pathways and acting as a partial IL6ST (gp130) agonist, independent of IL6Rα. In human kidney organoids, C3-LHF1 induced JAK/STAT3 signaling, amplified TNFα-driven CXCL10 secretion, and reduced podocyte marker expression, suggesting a role in tissue remodeling. These findings reveal unanticipated complexity in complement-mediated signaling and provide a comprehensive atlas of protein N-termini in human plasma, which enables discovery of novel immunoregulatory mechanisms and therapeutic targets in inflammatory disease.