A multitherapy single-cell atlas reveals cell type-specific modulation in sepsis-induced liver injury.

Sepsis-induced liver injury involves profound immune dysregulation. Natural compounds such as artesunate (ART), capsaicin (CAP), and oridonin (ORI) have demonstrated efficacy in mitigating systemic inflammation; however, their comparative cellular mechanisms in sepsis remain poorly characterized. Here, we integrated and reanalyzed the single-cell transcriptomic datasets of murine livers from 5 conditions: healthy control, sepsis, and sepsis treated with ART, CAP, or ORI. We uncover a spectrum of neutrophil subtypes with treatment-responsive phenotypes, including anti-inflammatory Ngp+ Neu1, immunosuppressive Cd274+ Neu2, and mature Stfa2l1+ Neu4, in which the excessive neutrophil expansion was suppressed by all 3 therapies through distinct regulon activities. Macrophages were activated and infiltration to partially rebalance immune homeostasis. Endothelial cells underwent profound reprogramming under sepsis, marked by NF-κB activation and oxidative stress, which are selectively modulated by treatment. Cell-cell communication analysis revealed a convergent dampening of inflammatory ligand-receptor networks, including the CCL signaling axis, and therapy-specific enhancement of regenerative cues, such as EGF signaling. Our findings reveal both shared and compound-specific immunoregulatory effects of ART, CAP, and ORI, offering mechanistic insights into hepatic immune rebalancing in sepsis. This single-cell atlas provides a conceptual framework for the rational design of multitarget therapies and highlights the key immune modules amenable to therapeutic intervention.