Silencing of S100A11 attenuates murine metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by insulin resistance and impaired hepatic metabolism, which lead to steatosis and lipotoxicity. S100A11, an alarmin upregulated in MASH, promotes steatosis in vitro, but its role in vivo remains unclear. We hypothesized that S100A11 drives MASH by upregulating hepatic lipid synthesis. Using whole-body <i>S100a11</i> knockout (<i>S100a11</i> ^<i>-/-</i> ) mice on a MASH-inducing diet, we found <i>S100a11</i> deficiency reduced steatosis, inflammation, and fibrosis. Hepatotropic AAV8-mediated silencing of <i>S100a11</i> confirmed these findings. Bulk RNA sequencing with Ingenuity Pathway Analysis revealed dysregulated carbohydrate and lipid metabolism in <i>S100a11</i> ^<i>-/-</i> livers, including downregulation of hexokinase 2 (<i>Hk2</i>). Since hexokinases regulate glucose flux into downstream metabolic processes, we overexpressed HK2 in <i>S100a11</i> ^<i>-/-</i> mice, which was sufficient to increase steatosis. Further, palmitate-induced HK2 upregulation required S100A11 in a human hepatocyte cell line. These studies identify HK2 as a downstream target of S100A11, both of which are potential therapeutic targets for MASH.