Beyond ACE2: DPP4 Engagement Redefines SARS-CoV-2 Receptor Tropism

The continued evolution of SARS-CoV-2 has produced variants with enhanced transmissibility despite reduced binding affinity to the canonical entry receptor ACE2, suggesting the involvement of additional host factors. Here, we integrate large-scale sequence analysis, structure-informed machine learning, biochemical assays, cell-based entry models, and in vivo infection studies to examine receptor usage diversification in recent SARS-CoV-2 variants. We find that multiple post-Omicron lineages, including XBB-derived variants, exhibit increased functional engagement of dipeptidyl peptidase 4 (DPP4), accompanied by reduced reliance on ACE2-mediated entry in defined experimental contexts. In human DPP4 knock-in mice, representative XBB variants display enhanced replication with limited pulmonary pathology. Together, these findings support a model in which SARS-CoV-2 evolution is characterized by diversification of receptor engagement strategies, highlighting DPP4 as a functionally relevant entry factor that may contribute to viral fitness under immune pressure.