Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

Gandhi, A.; Lande, K.; Li, Y.; Hoffman, F. A.; LaPorte, M.; Tan, S.; Evensen, G.; Portillo, B.; Teneche, M. G.; Arnold, R.; Rajesh, A.; Proulx, J.; Yin, S.; Havas, A. P.; Miciano, C.; Yang, Q.; Smoot, E.; Mamde, S.; Davis, A.; Yip, K.; Wang, A.; Ren, B.; Williams, A.; Kaech, S.; Adams, P. D.

doi:10.64898/2025.12.20.695732

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bioRxiv · 10.64898/2025.12.20.695732

Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

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Abstract

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-{gamma} response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

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Gandhi, A., Lande, K., Li, Y., Hoffman, F. A., LaPorte, M., Tan, S., Evensen, G., Portillo, B., Teneche, M. G., Arnold, R., Rajesh, A., Proulx, J., Yin, S., Havas, A. P., Miciano, C., Yang, Q., Smoot, E., Mamde, S., Davis, A., Yip, K., Wang, A., Ren, B., Williams, A., Kaech, S., Adams, P. D.. 2025-12-22. Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.. https://doi.org/10.64898/2025.12.20.695732

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