{
  "id": 10487996,
  "title": "The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.",
  "url": "https://urgent.news/2026/09/28/the-p53-p21-cyclin-d2-regulatory-axis-drives-metabolic-reprogramming",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-28T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753597v1?rss=1"
  },
  "original_language": "en",
  "account": "Aging contributes to chronic diseases by creating senescent cells, such as macrophages, that promote inflammation. Macrophages can be divided into two functional groups: canonical p16-high cells, which can either cause cancer or provide disease tolerance, and a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). Until now, the molecular mechanisms behind this specific senotype remained unclear.\n\nTo investigate this, researchers employed genetic and multi-omic techniques. Their findings reveal that a p53-p21-dependent program actively suppresses p16, which is crucial for the survival of senescent macrophages. The study also identifies Cyclin D2 as a non-canonical downstream effect of this program. Cyclin D2 moves from the nucleus to mitochondria and lipid droplets, partnering with MIC60 to orchestrate metabolic reprogramming and influence AKT1-mTORC1 signaling, which sustains the senescence-associated secretory phenotype (SASP). In mice and humans with MASLD, there is an increase in double-positive macrophages that express both Cyclin D2 and p21. Selective depletion of these double-positive macrophages through senolytic treatment can mitigate the disease.\n\nIn summary, the research highlights a druggable p53-p21-Cyclin D2 axis that defines the macrophage senotype during aging and MASLD. This discovery could pave the way for novel therapeutic strategies to target and treat these conditions.",
  "summary": "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…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}