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Advances in Radiotherapy
& Nuclear Medicine Aspirin’s protective effect on RISI

that the arrested cells may be preparing for an immune- DNA repair pathways and modulation of inflammatory
related response or stress adaptation. responses.
In contrast, the Irra_Cycling cells showed significant 4. Discussion
enrichment in pathways related to metabolism, DNA
repair, and cell cycle progression. Specifically, pathways The findings of this study demonstrate that ASP pre-
such as “homologous recombination,” “non-homologous treatment has significant prophylactic effects against
end joining,” “DNA replication,” and “cell cycle” were highly RISI in a mouse model. Our results indicate that ASP
enriched in cycling cells, suggesting a focus on cellular not only reduces the severity of RISI but also promotes
recovery, enhanced DNA repair mechanisms, and division. the recovery of IFE cells through mechanisms that may
Notably, pathways such as “pyrimidine metabolism” and involve enhanced DNA repair and modulation of cell
“purine metabolism” were also upregulated, pointing to cycle dynamics. This study represents a comprehensive
active nucleotide synthesis needed for cell proliferation. effort to explore the protective effect of ASP at both the
molecular and cellular levels, with implications for its
These distinct pathway differences suggest that
irradiated arrested cells are largely engaged in immune and potential clinical application as an adjunct therapy during
radiotherapy.
stress responses, whereas the corresponding cycling cells
are focused on DNA repair and metabolic activity, aiming One of the key findings in this study is the reduction
for proliferation and tissue recovery. We hypothesize in overall RISI severity in ASP-treated mice, as
that following irradiation, IFE C cells either enter an evidenced by delayed onset, reduced peak scores, and a
arrest state due to DNA damage or successfully repair shortened duration of high-severity injury. These effects
the damage and re-enter the cell cycle. The activation of are particularly striking when viewed alongside our
DNA repair pathways, such as homologous recombination comprehensive scoring system, which provides a detailed
and non-homologous end joining, likely promotes the assessment of RISI progression. This detailed assessment
recovery of these cells and contributes to the resolution allowed us to differentiate multiple phases of injury
of RISI (Figure S2). progression and identify the specific points at which
ASP exerted its beneficial effects. The reduction in peak
3.6. ASP’s effect on RISI progression RISI severity and the shortened duration of high injury
To further understand the impact of ASP on RISI, we levels are likely driven by ASP’s ability to modulate the
evaluated RISI severity using daily recorded scores and inflammatory response and promote effective DNA repair
performed additional analyses (Figure 5). (Figure 5). These observations are consistent with previous
studies that have reported anti-inflammatory effects and
The trend of RISI scores over time indicated that 5,22
the peak RISI score was significantly lower in the ASP- DNA repair properties of ASP .
treated group compared to the untreated control group, The differential gene expression analysis of irradiated
demonstrating a reduction in injury severity by the versus control groups provided important insights
treatment. Specifically, the peak RISI score in the untreated into the molecular changes induced by radiation. The
group was approximately 30, whereas the ASP-treated irradiated group exhibited significant transcriptional
group peaked at around 20 (Figure 5A). The time taken reprogramming, with a large number of genes associated
for each group to reach a significant RISI score threshold with extracellular matrix organization and immune
(>3.5) showed no significant difference between the regulation being upregulated, while metabolic processes
two groups (Figure 5B). However, the mean RISI scores were downregulated. These findings suggest that radiation
between days 18 and 20 were notably lower in the ASP- induces a stress response that shifts cellular focus from
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treated group compared to the corresponding untreated normal metabolic activity to survival and adaptation .
controls, suggesting that ASP effectively reduced the injury ASP treatment, by mitigating the inflammatory response
severity during the peak period (Figure 5C). The duration and potentially reducing the extent of tissue damage, may
for which the RISI score remained above the threshold of help preserve the normal cellular environment, thereby
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3.5 was significantly shorter in the ASP-treated group than preventing excessive tissue remodeling and fibrosis .
in the untreated group, indicating that ASP reduced the The cell subtype annotation analysis and pseudotime
period of severe injury (Figure 5D). trajectory mapping provide additional insights into the
These findings suggest that ASP pre-treatment provides role of ASP in protecting skin cells from radiation-induced
a significant protective effect against RISI, reducing both damage. We observed that the IFE C cells, identified as the
the peak severity and the duration of high injury levels. cycling population among the IFE subtypes, were located
This effect is likely mediated through the activation of at the upstream end of the differentiation trajectory. This

Volume 3 Issue 1 (2025) 66 doi: 10.36922/arnm.5829