Lipotoxicity Amplifies IL‐6 Trans‐Signaling in Sinusoidal Endothelial Cells to Promote Endotheliopathy and Liver Injury

ABSTRACT Background and Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) affects approximately 25% of the global population and is a major health concern. Liver sinusoidal endothelial cells (LSECs) undergo morphological and functional alterations during MASLD progression, resulting in endotheliopathy characterized by pro‐inflammatory phenotypes. We hypothesize that lipotoxicity synergistically exacerbates LSEC dysfunction in MASLD via IL‐6 trans‐signaling. Methods Human adipocytes were treated with palmitic acid (PA). Human LSECs were treated with PA and the IL‐6/soluble IL‐6 receptor (sIL‐6R) complex. Western blotting, qRT‐PCR, RNA sequencing, transwell assays, and immunofluorescence were performed to examine inflammatory responses. MASLD model mice were established using a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) to validate the in vivo results. Alterations in LSEC morphology were examined by western blotting, histology, and electron microscopy. Results PA promoted IL‐6 secretion from adipocytes. In LSECs, PA increased NFκB phosphorylation, whereas co‐stimulation with PA and IL‐6/sIL‐6R complex synergistically enhanced activator of transcription 3 (STAT3) phosphorylation and upregulated inflammatory cytokines, chemokines, and adhesion molecules, including VCAM1. Furthermore, RNA sequencing showed concurrent NFκB and Janus kinase (JAK)/STAT pathway activation. This synergistic effect promoted neutrophil migration and VCAM1 expression under in vitro conditions. In the MASLD mouse model, hepatic IL‐6 expression was elevated, accompanied by steatosis, increased transaminase levels, and inflammatory cell infiltration, along with increased VCAM1 expression and sinusoidal capillarization characterized by upregulated CD34 and downregulated CD32b and LYVE‐1. Conclusion Lipotoxicity‐amplified IL‐6 trans‐signaling synergistically exacerbates LSEC endotheliopathy and promotes leukocyte recruitment and liver injury, contributing to MASLD progression and providing novel insights into its pathogenesis.