The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.

Torres, G.; Salladay-Perez, I. A.; Deng, C. Y.; Avila, I.; Delgado, Y.; Tong, G.; Munoz-Estrada, J.; Estrada, L.; Dhingra, A.; Armstrong, W. R.; Singh, A.; Cooper, I.; Enriquez, E.; Kaushal, P.; Ni, J.; Chowdhury, K.; Pan, C.; Stiles, L.; Beninca, C.; Hui, S. T.; Krall, A.; Christofk, H.; Lusis, A. J.; O'Sullivan, T. E.; Meyer, J. G.; Singh, R.; Tornini, V. A.; Shirihai, O. S.; Bouhaddou, M.; Covarrubias, A. J.

doi:10.64898/2026.09.22.753597

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bioRxiv · 10.64898/2026.09.22.753597

The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.

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Abstract

Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.

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Torres, G., Salladay-Perez, I. A., Deng, C. Y., Avila, I., Delgado, Y., Tong, G., Munoz-Estrada, J., Estrada, L., Dhingra, A., Armstrong, W. R., Singh, A., Cooper, I., Enriquez, E., Kaushal, P., Ni, J., Chowdhury, K., Pan, C., Stiles, L., Beninca, C., Hui, S. T., Krall, A., Christofk, H., Lusis, A. J., O'Sullivan, T. E., Meyer, J. G., Singh, R., Tornini, V. A., Shirihai, O. S., Bouhaddou, M., Covarrubias, A. J.. 2026-09-28. The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.. https://doi.org/10.64898/2026.09.22.753597

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