# Senescence-Driven Inflammation and Immune Dynamics in the Progression of Radiation Cystitis

## TL;DR

This study explores how radiation-induced cell aging and immune changes contribute to bladder inflammation and dysfunction in radiation cystitis.

## Contribution

The study identifies immune and senescence-driven mechanisms during the latent phase of radiation cystitis, previously unanalyzed.

## Key findings

- Latent and chronic phases of RC are marked by distinct inflammatory signaling and cytokine profiles.
- Persistent Cdkn1a (P21) upregulation indicates sustained senescence during RC progression.
- Immune shifts and SASP proteins correlate with bladder dysfunction in chronic RC.

## Abstract

Pelvic radiation therapy is an essential treatment for several pelvic malignancies, but it can lead to radiation cystitis (RC), a severe progressive inflammatory bladder disorder lacking effective diagnosis and therapeutic options. RC evolves through acute, latent, and chronic phases, ultimately resulting in bladder fibrosis, vascular damage, and hematuria. Here, we characterize the molecular and immunological features associated with RC progression using a preclinical mouse model. Building on a prior analysis of the acute and chronic phases, we examined the previously unanalyzed latent phase and integrated transcriptomics, immune cell profiling, inflammatory protein measurements, and bladder function assessments across all stages. Acute radiation injury was marked by the strong activation of apoptotic pathways, whereas latent and chronic phases were dominated by inflammatory signaling with distinct cytokine and chemokine signatures. The persistent upregulation of Cdkn1a (P21) was consistent with sustained senescence-associated signaling, while reductions in IL-27 and shifts in the granulocyte–lymphocyte-enriched immune population during the latent phase were consistent with altered immune regulatory states. At chronic stages, increased SASP-associated proteins and matrix remodeling mediators coincided with bladder functional decline. Together, these findings support a model in which radiation-induced senescence, coupled with immune dysregulation during the latent phase, are coordinated features accompanying inflammation, tissue remodeling, and bladder dysfunction in RC.