Myeloid UCHL1 deficiency ameliorates sepsis-induced liver injury by suppressing M1 macrophage polarization via targeting Gpi ubiquitination.

Ubiquitin C-terminal hydrolase 1 (UCHL1), a critical deubiquitinating enzyme (DUB), cleaves ubiquitin/polyubiquitin chains from substrate proteins andhas been shown to promoteoxidative stress and inflammatory response. However, UCHL1's precise role in sepsis-induced liver injury (SILI) pathogenesis remains unknown. Here, we show elevated UCHL1 in cecal ligation puncture (CLP)-induced livers and lipopolysaccharide (LPS)-treated bone marrow-derived macrophages (BMDMs). Deficiency or pharmacological inhibition of UCHL1 with LDN-57444 (LDN) conferred protection against SILI by inhibiting oxidative stress and M1 macrophage polarization through targeting the degradation of glucose-6-phosphate isomerase (Gpi) and suppressing Gpi-mediated glycolysis. In contrast, the overexpression of Gpi reversed the inhibitory effects of UCHL1 deficiency on sepsis. Bone marrow transplantation combined within vitrostudies further showed that myeloid UCHL1 deficiency similarly improved SILI through suppression of Gpi stabilization and glycolysis. Hence, targeting UCHL1 in myeloid cells emerged as a protective strategy against SILI, highlighting its potential as a novel therapeutic avenue for patient care.