FASEB J. 2026 Sep 30;40(18):e72297. doi: 10.1096/fj.202603249R.
ABSTRACT
Lupus nephritis (LN) is a critical complication of systemic lupus erythematosus (SLE) and a leading cause of mortality in those affected. Abnormal energy metabolism of macrophages is closely associated with LN pathogenesis. Adenosine diphosphate (ADP) is known to regulate macrophage proinflammatory function; however, its specific role in SLE progression remains unexplored. We employed a spontaneous SLE mouse model and an integrated transcriptomic and metabolomic approach to investigate the effect of ADP on SLE disease progression and macrophage function. Our study revealed that ADP stimulates the AMPK signaling pathway, curtails macrophage senescence, and diminishes the release of senescence-associated secretory phenotype factors, ultimately alleviating SLE progression. Mechanistically, ADP promotes KLF10 expression, which binds to Sirtuin1 to facilitate deacetylation at the promoter region of Cdkn1a in macrophages. This process leads to reduced p21 expression and macrophage senescence. Collectively, the findings uncover a novel regulatory role of ADP in the pathogenesis of SLE and macrophage senescence, indicating its potential as a target for treatment.
PMID:42776065 | DOI:10.1096/fj.202603249R