Identification of CD38 ^high Monocyte as a Candidate Diagnostic Biomarker and Therapeutic Target for Sepsis

Abstract Sepsis is characterized by a systemic host response to infection. Monocytes, as major mediators of acute infection, are implicated in complications among critically ill patients. Identifying key monocyte subsets and their activation states is essential for diagnosis and delineating new therapeutic targets for sepsis. Here, single cell transcriptome sequencing and mass cytometry are used to assess alterations in the composition and function of peripheral monocytes of patients with sepsis, and CD38 ^high monocytes in circulation are specifically accumulated within the first 24 h of sepsis. CD38 ^high monocytes are detectable by conventional flow cytometry to discriminate sepsis and sterile inflammation, and are associated with 28‐day mortality in bacterial sepsis. Targeting CD38 therapy markedly reduces inflammatory response in primary monocytes and in sepsis mice model. Mechanistically, CD38 ^high monocytes in sepsis exhibit hyperactivated glycolysis with activation of hypoxia‐inducible factor‐1α (HIF‐1α) due to NAD ⁺ consumption. Glycolytic metabolite methylglyoxal (MGO) is found to regulate expression of CD38, establishing a CD38‐HIF‐1α/glycolysis/MGO loop that exacerbates sepsis‐induced immune dysregulation. These findings demonstrate that CD38 ^high monocytes might serve as a candidate diagnostic biomarker and therapeutic target for sepsis.