p53–p21–Cyclin D2 axis in senescent macrophages during aging and MASLD
In this abstract, a p53–p21 program represses p16 in senescent macrophages; Cyclin D2 moves to mitochondria and lipid droplets, and Cyclin D2–p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis. [1]
Automatic summary · not editorially reviewed
The key findings
A p53–p21-dependent program actively represses p16 and is required for senescent macrophage viability. [1]
p16 repression promotes survival during acute genotoxic stress but is dispensable for cell-cycle arrest and core senescence features in macrophages. [1]
Cyclin D2–p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis and can be targeted by senolytics. [1]
The source at a glance
- Study type / format
- Preclinical and human-tissue research abstract
- Population / context
- Senescent macrophages in mice and human liver cirrhosis, as described in the abstract.
- Summary based on
- Study abstract
- Publication status
- Preprint · peer-review status not confirmed
- Original publication
- September 28, 2026
p53–p21 program represses p16 in macrophages
The authors describe senescent macrophages as functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance. They had previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD), but its molecular basis was undefined. Using genetic and multi-omic approaches, they report that a p53–p21-dependent program actively represses p16 and is required for senescent macrophage viability. They also state that p16 repression promotes survival during acute genotoxic stress but is dispensable for cell-cycle arrest and core senescence features in macrophages.
Supporting source [1]
Cyclin D2 relocalizes and engages MIC60 and AKT1-mTORC1
The abstract identifies Cyclin D2 as a non-canonical downstream effector of this program. It redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming. Cyclin D2 also modulates AKT1-mTORC1 signaling that sustains the senescence-associated secretory phenotype (SASP). These are described findings from genetic and multi-omic experiments; the abstract does not report which specific assays or models were used for each step.
Supporting source [1]
Double-positive macrophages in mice and human cirrhosis
Cyclin D2–p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, according to the abstract. They can be selectively depleted by senolytic treatment. The authors conclude that these findings define a druggable p53–p21–Cyclin D2 axis that specifies macrophage senotype. This is an abstract only; the full text was not reviewed, so study design details, sample sizes, follow-up and the extent of human data cannot be assessed here.
Supporting source [1]
How to interpret this
Abstract only; the full text was not reviewed. Design details, sample sizes, follow-up and the extent of human data are not reported in the abstract. Findings are associations and experimental results, not established human treatments.
Based on the study abstract; the full paper, tables and supplementary data were not reviewed.
Source & supporting passages
Torres G, Salladay-Perez IA, Deng CY, Avila I, Delgado Y, Tong G, Muñoz-Estrada J, Estrada L, Dhingra A, Armstrong WR, Singh A, Cooper I, Enriquez E, Kaushal P, Ni J, Chowdhury K, Pan C, Stiles L, Beninca C, Hui ST, Krall AS, Christofk HR, Lusis AJ, O’Sullivan TE, Meyer JG, Singh R, Tornini VA, Shirihai OS, Bouhaddou M, Covarrubias AJ. · europepmc.org · September 28, 2026