ER stress upregulates S100A11 in steatohepatitis models via epigenetic modifications within the lipotoxicity-influenced enhancer

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by complex interactions between lipotoxicity, ER stress responses, and immune-mediated inflammation. We identified enrichment of the proinflammatory alarmin S100 calcium-binding protein A11 (S100A11) on extracellular vesicles stimulated by palmitate-induced lipotoxic ER stress with concomitant upregulation of hepatocellular S100A11 abundance in an IRE1A-XBP1s-dependent manner. We next investigated the epigenetic mechanisms that regulate this stress response. Publicly available human liver ChIP-Seq GEO datasets demonstrated a region of histone H3 lysine 27 (H3K27) acetylation upstream of the S100A11 promoter. H3K27 acetylation ChIP-qPCR demonstrated a positive correlation between lipotoxic ER stress and H3K27 acetylation of the region, which we termed the lipotoxicity-influenced enhancer (LIE) domain. CRISPR-mediated repression of the LIE domain reduced palmitate-induced H3K27 acetylation and corresponding S100A11 upregulation in Huh7 cells and immortalized mouse hepatocytes. Silencing of the murine LIE in 2 independent steatohepatitis models demonstrated reduced S100a11 upregulation and attenuated liver injury. We confirmed H3K27 acetylation and XBP1s occupancy at the LIE domain in human MASH liver samples and an increase in hepatocyte-derived S100A11-enriched extracellular vesicles in MASH patient plasma. Our studies demonstrate a LIE domain that mediates hepatic S100A11 upregulation. This pathway may be a potential therapeutic target in MASH.