Rapamycin treatment in arthritic mice revealed that neuropeptide Y connects cellular senescence and inflammation pathways in rheumatoid arthritis, and silencing NPY in joint cells reduced key inflammatory cytokines.
NPY silencing reduced TNF-α, IL-1β, and IL-6When neuropeptide Y was silenced in arthritic joint lining cells, all three major inflammatory cytokines of the senescence-associated secretory phenotype dropped significantly — demonstrating NPY's role as a driver of joint inflammation.
What the researchers found
Transcriptomic analysis of rapamycin-treated arthritic mice identified neuropeptide Y (NPY) as a differentially expressed gene connecting senescence and inflammation pathways. Rapamycin reduced NPY protein levels along with TNF and the senescence marker β-galactosidase, and also modulated NPY receptor expression (NPY1R, NPY2R) and autophagy genes (Sirt1, Sirt6, Lc3b).
In vitro validation showed that silencing NPY in fibroblast-like synoviocytes (the cells lining arthritic joints) significantly reduced expression of three major inflammatory cytokines — TNF-α, IL-1β, and IL-6 — which are the hallmarks of the senescence-associated secretory phenotype (SASP). NPY silencing also downregulated its own receptors and increased Sirt1 expression, a longevity-associated gene.
Why it matters
Rheumatoid arthritis affects about 1% of the global population, and current treatments focus on broadly suppressing the immune system. Identifying NPY as a molecular connector between cellular aging and joint inflammation opens a more targeted therapeutic avenue. If NPY or its receptors can be selectively modulated, it could address both the inflammatory and degenerative aspects of arthritis simultaneously — something current treatments don't achieve.
How the study worked
Collagen-induced arthritis was established in DBA/1 mice, followed by 40 days of rapamycin treatment. RNA sequencing and bioinformatic analyses identified differentially expressed genes and altered pathways. Results were validated by RT-qPCR and immunohistochemistry. Functional assays using NPY gene silencing in fibroblast-like synoviocytes (FLS) confirmed the peptide's role in regulating inflammatory and senescence pathways.
What this study cannot tell us
This is a preclinical study using a collagen-induced arthritis mouse model, which doesn't fully replicate human RA. The in vitro NPY silencing experiments were performed in isolated synoviocytes, which may behave differently in the complex joint environment. The study did not test whether directly targeting NPY in vivo (rather than using rapamycin) would reduce arthritis severity. Rapamycin has broad effects, so the specific contribution of NPY modulation to the overall therapeutic effect is unclear.
How to read the evidence
This is a preclinical study combining in vivo mouse arthritis modeling with transcriptomic analysis and in vitro functional validation. The multi-method approach (RNA-seq, qPCR, immunohistochemistry, gene silencing) strengthens the findings, though translation to human RA requires further study.
When this study was published
Published in 2025, this is a very recent study contributing to the rapidly evolving field of senescence-targeted therapeutics (senolytics/senomorphics) for inflammatory diseases.
The bigger picture
Cellular senescence has emerged as a major driver of age-related diseases, and the senescence-associated secretory phenotype (SASP) is increasingly recognized as a key source of chronic inflammation. This study adds NPY to the growing list of peptide mediators connecting senescence and inflammation, and positions it within the mTOR/rapamycin signaling network. The finding that NPY regulates sirtuins and autophagy genes connects it to fundamental aging biology, suggesting relevance beyond arthritis to other age-related inflammatory conditions.
Questions still open
- Would directly blocking NPY or its receptors in arthritic joints reduce disease severity without the broad immunosuppressive effects of rapamycin?
- Is NPY elevation a cause or consequence of cellular senescence in rheumatoid arthritis synovial tissue?
- Does the NPY-senescence-inflammation axis operate similarly in other age-related inflammatory diseases like osteoarthritis or inflammatory bowel disease?
Common questions
What is neuropeptide Y and what does it normally do?
What is the senescence-associated secretory phenotype (SASP)?
Read the original research
Rapamycin reveals neuropeptide Y as a regulator of senescence and inflammatory pathways in arthritis.
Neuropeptides, 112, 102533
Citation
González-Chávez, Susana Aideé; Chaparro-Barrera, Eduardo; Loya-Rivera, Mario; Rodríguez-Castillo, Alejandra Jazmín; Prieto-Carrasco, Rodrigo; Aguilera, Renato J; Betancourt, Ana P; Mohl, Jonathon E; Ruizesparza-Hinojos, Daniel Alberto; Ramírez-Pérez, Sergio de Jesús; Bermúdez, Mercedes; Pacheco-Tena, César. (2025). Rapamycin reveals neuropeptide Y as a regulator of senescence and inflammatory pathways in arthritis.. Neuropeptides, 112, 102533. https://doi.org/10.1016/j.npep.2025.102533