Immunometabolic modulation in sepsis: DHCR24 inhibition as a therapeutic strategy

Sepsis is a life-threatening condition caused by a dysregulated host response to infection and represents one of the leading causes of mortality worldwide. In addition to excessive inflammation, sepsis is characterized by profound alterations in immune and metabolic pathways, which contribute to impaired host defence and organ dysfunction. Recently, increasing attention has been directed toward immunometabolic mechanisms linking lipid metabolism to the regulation of inflammatory responses, and among these, cholesterol metabolism has emerged as a relevant modulator of innate immunity and inflammatory signalling. The aim of this study was to investigate the effects of pharmacological DHCR24 inhibition in experimental sepsis and to explore its potential role in immunometabolic regulation during systemic inflammation. DHCR24 is a key enzyme in cholesterol biosynthesis, and its inhibition leads to the accumulation of desmosterol, a sterol intermediate involved in immune regulation. To evaluate the impact of DHCR24 inhibition during sepsis, the selective inhibitor SH42 was administered in preventive and acute treatment regimens in female and male APOE*3-Leiden.CETP mice using a cecal slurry model of sepsis. Clinical parameters associated with disease progression were monitored throughout the study. In addition, inflammatory responses and immune cell populations were investigated through molecular and immunological analyses, including immunohistochemistry, quantitative PCR, and flow cytometry. Overall, this work highlights the relevance of immunometabolic pathways in sepsis and supports a potential role for DHCR24 inhibition in the modulation of inflammatory and immune responses. These findings contribute to the understanding of the relationship between cholesterol metabolism and innate immunity during systemic infection and identify DHCR24 as a promising target for further investigation in sepsis and inflammatory diseases.