Integrated cross-organ transcriptomic analysis uncovers conserved gene signatures predictive of allograft rejection

Long-term transplant success is limited by allograft rejection, a complex process traditionally studied on an organ-specific basis. To establish a unified framework beyond organ-specific studies, we performed a network-based systems biology analysis of transcriptomic data from 672 liver, kidney, and heart transplant biopsies to identify a conserved, pan-organ molecular framework of rejection. By constructing and comparing organ-specific gene co-expression networks, we identified a consensus, six-module immune cascade that captures the hierarchical nature of the alloimmune response. In addition, we also uncovered a highly conserved 24-gene cell cycle signature consistently upregulated in rejecting allografts, implicating cellular proliferation as a core feature of rejection pathology. From this framework, we derived a 172-gene immune signature and applied machine learning models to assess its predictive performance, achieving accuracy comparable to established benchmarks. We further refined this to a minimal, high-performance 20-gene immune signature (AUC > 0.96). Both the immune and cell cycle signatures demonstrated robust, pan-organ utility when independently validated in a lung transplant cohort (n = 243). Collectively, these findings define a pan-organ molecular framework for rejection and highlight cell cycle dysregulation as a conserved hallmark, offering a foundation for standardized, cross-organ diagnostic platforms to improve allograft surveillance and patient outcomes.