CYP1B1-Mediated Metabolic Reprogramming Drives Immune Dysregulation in Sepsis: A Single-Cell Transcriptomic and Therapeutic Exploration

Sepsis, a life-threatening condition characterized by dysregulated immune responses, poses significant clinical challenges due to high mortality and limited therapeutic strategies. Emerging evidence highlights immune-metabolic dysregulation, particularly in monocytes and macrophages, as a critical driver of sepsis pathogenesis. Here, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from patients with sepsis and healthy controls, revealing significant alterations in immune cell composition. Sepsis patients exhibited increased myeloid cells and decreased T, NK, and B/plasma cells. CD8+ T cells displayed enhanced activation, while macrophages showed disrupted amino acid metabolism, with upregulated tryptophan pathways (e.g., CYP1B1, HADHA) and downregulated arginine and proline metabolism. In vitro, lipopolysaccharide (LPS)-stimulated macrophages exhibited elevated CYP1B1 expression, and its inhibition by (E)-2,3',4,5'-tetramethoxystilbene (TMS) suppressed pro-inflammatory cytokine production (IL1B, TNFA). In a murine sepsis model, TMS administration reduced systemic inflammation, attenuated organ damage, and decreased myeloid cell infiltration. These findings identify CYP1B1 as a novel metabolic checkpoint in sepsis-associated hyperinflammation and demonstrate the therapeutic potential of TMS in rebalancing immune dysregulation. Our study provides insights into precision immunometabolic interventions for sepsis management.