A CFLAR–RIPK1 autophagy checkpoint in dendritic cells drives immune dysfunction in sepsis

Sepsis‑induced immune dysfunction is shaped, in part, by dendritic‑cell (DC) defects in autophagy. Whether CASP8 and FADD-like apoptosis regulator (CFLAR) and Receptor-interacting protein kinase 1 (RIPK1) coordinate DC autophagy in sepsis remains unclear. Here, we combine patient single‑cell RNA‑seq and a clinical cohort with LPS‑stimulated bone‑marrow DCs and murine cecal ligation and puncture to delineate a CFLAR–RIPK1–autophagy axis. Gain‑ and loss‑of‑function, co‑immunoprecipitation and ubiquitination assays show that CFLAR interacts with RIPK1, limits its ubiquitin‑dependent turnover, and restrains autophagic flux (LC3‑II turnover, p62 clearance). As a consequence, DC maturation and cytokine programs are blunted and DC–CD4⁺ T‑cell priming is skewed; RIPK1 silencing reverses these effects. In vivo, reducing CFLAR increases RIPK1 ubiquitination, restores autophagy, improves antibacterial control and attenuates organ injury in sepsis. These data identify CFLAR as an upstream brake on RIPK1‑linked DC autophagy and adaptive immune priming, providing a mechanistic entry point for modulating sepsis‑associated immunoparalysis.