Transient but not sustained p53 activation by targeting METTL3 prevents radiation-induced intestinal injury through dual-regulation of revival stem cells.

Radiation-induced intestinal injury (RIII) remains a severe complication of radiotherapy. Although p53 activation is known to be protective, no clinically available p53 activators exist. Different p53 activation dynamics (transient or sustained) are linked with radio-sensitivity, yet their therapeutic relevance to RIII has not been explored. The emerging role of N6-methyladenosine (m6A) in radiation injury is recognized, but the mechanistic link between m6A and p53 signaling in RIII remains elusive. Here, we investigated how m6A regulates p53 signaling, as well as the functional consequences and mechanisms of transient or sustained p53 activation via pharmacologically targeting m6A in RIII. After radiation, m6A writer METTL3 increases m6A on MDM2 mRNA, which is recognized by m6A reader IGF2BP3, upregulating MDM2 and suppressing intestinal p53. Then, METTL3 inhibitor S-Adenosylhomocysteine (SAH) was used to induce transient or sustained p53 activation. Functionally, a single dose of SAH suppressed MDM2 and induced transient p53 activation, thereby protecting against RIII, whereas multiple dosing induced sustained p53 activation but failed to confer a protective benefit. Mechanistically, transient p53 activation prevented RIII by stimulating YAP signaling and revival stem cells (revSCs) regeneration, a newly defined stress-induced intestinal stem cell population, whereas sustained p53 activation failed to. Importantly, SAH did not protect colorectal cancer cells from radiation. Together, these findings reveal that radiation inhibits intestinal p53 expression through the METTL3/m6A/IGF2BP3/MDM2 axis, and that transient p53 activation via METTL3 inhibition offers a promising protective strategy for RIII through YAP-mediated revSCs regeneration.