Hepatocyte CD44 drives IL6/STAT3-high neighborhoods linked to blunted T-cell effector function in the aged liver

Liver cancer incidences increase beyond 55 years of age suggesting that molecular, cellular and tissue changes accompanying aging contribute critically to tumor initiation. However, the mechanisms linking aging and liver cancer initiation are not well understood. Our study investigates the role of CD44, a transmembrane glycoprotein and a known marker of tumor-initiating cells (TICs), in age-associated liver pathophysiology. Aged livers showed an accumulation of CD44 expressing hepatocytes. Single nucleus RNA sequencing revealed that CD44 expressing hepatocytes in aged livers exhibit enrichment of immune modulatory genes and activation of the IL6/JAK/Stat3 pathway. Spatial analyses confirmed upregulation of the IL6/JAK/Stat3 pathway and showed that CD44-expressing hepatocytes are proximal to T-cell neighborhoods exhibiting reduced cytokine expression. In adoptive transfer assays, ex vivo-activated CD8+ T cells mounted a lower antigen-specific IFNg response in aged livers than in young liver, consistent with an immune suppressive aged milieu. Hepatocyte-specific loss of Cd44 expression in aged livers compromised IL6/JAK/Stat3 activity and other immune/fibrotic gene signatures, supporting a contribution of hepatocyte Cd44 to age-associated immune dysregulation and early fibrosis. Our findings identify an aging-associated hepatocyte CD44 state with IL6/JAK/Stat3 activation, blunted T cell effector signals and early fibrotic cues.