CHD1 regulates the inflammatory response in macrophages and functions as a pharmacological target during sepsis.

Inflammation is a defining feature of sepsis and a major determinant of disease progression, organ dysfunction, and mortality. Excessive inflammatory responses during the early stage not only cause direct tissue injury but also shape subsequent immune suppression. Macrophages are central orchestrators of this early immune response; however, the molecular regulators that govern macrophage activation in sepsis remain incompletely understood. In this study, integrated bioinformatic analyses of lipopolysaccharide (LPS)-stimulated macrophages combined with experimental validation were performed to identify key regulatory factors and elucidate the underlying mechanisms driving inflammatory responses. An LPS-induced mouse model of sepsis was used to evaluate the therapeutic potential of pharmacological key factor inhibition. In addition, public transcriptomic datasets from sepsis patients were analyzed to assess the clinical relevance of its expression. The results demonstrated that CHD1 was identified as a previously unrecognized regulator of macrophage-driven inflammation in sepsis. CHD1 expression was induced in macrophages following LPS stimulation through the TLR4/MyD88 signaling axis. Mechanistically, CHD1 amplified pro-inflammatory cytokine production by interacting with NF-κB. Early pharmacological inhibition of CHD1 markedly improved survival and alleviated multi-organ injury in septic mice. Furthermore, analysis of clinical transcriptome datasets revealed that elevated blood CHD1 expression in early sepsis was associated with disease severity and poor prognosis. Collectively, this study identifies macrophage-derived CHD1 as a critical driver of inflammation in sepsis by selectively enhancing NF-κB-dependent inflammatory transcription. Targeting CHD1 represents a promising strategy for early intervention in sepsis and may provide both prognostic and therapeutic value.