Abstract: Radiotherapy plays a major role in the treatment of abdominal malignancies; however, it leads to the development of unintended side effects in the intestine like radiation-induced enteritis. Radiation injury inflames the intestinal mucosa and depletes the proliferative intestinal stem cells (ISCs). Following injury, intestinal regeneration relies on the proliferation of surviving ISCs and the dedifferentiation of progenitors and differentiated cells to replenish the stem cell pool. However, the consequences of this process remain poorly understood. Here, we demonstrate that intestinal cells recovering from radiation injury develop an epigenetic inflammatory memory and retain transcriptional features of their previous identity. Intestinal cells retain higher chromatin accessibility and elevated expression of inflammation-associated genes post-recovery, enabling faster bodyweight and cell proliferation recovery upon subsequent radiation exposure. However, the dedifferentiation process causes a broad loss of cellular identity across all intestinal cell types, driving them into a stem-like, highly plastic state, which compromises their functional specialization. Consequently, the progeny of de novo formed ISCs exhibit enhanced dedifferentiation capacity after secondary injury, at the expense of their ability to perform differentiated cell functions. This adaptive state supports rapid regeneration following recurrent injuries, but we hypothesize that it may predispose to long-term complications, such as chronic radiation-induced enteritis or cancer. These findings highlight the dual role of epigenetic memory and cellular plasticity in intestinal regeneration, offering new insights into the biology of ISCs and potential therapeutic targets to mitigate intestinal damage.
