miR-338-3p promotes radiation recall like dermatitis by suppressing pleiotrophin via the PI3K/Akt/Bcl2 pathway

Radiation recall dermatitis (RRD) is a rare but severe inflammatory reaction induced by certain drugs in previously irradiated skin, which can markedly impair quality of life and disrupt cancer treatment. However, the molecular mechanisms underlying RRD remain poorly understood. In this study, a radiation recall-like dermatitis model (RRLD) was established in Sprague-Dawley rats by localized skin irradiation followed by subcutaneous administration of non-toxic concentrations of chemotherapeutic agents, including 5-fluorouracil (5-Fu, 10 µg/µL) or Epirubicin (EPI, 0.05 µg/µL), into the irradiated area. Transcriptomic and miRNA sequencing of rat skin tissues from RRLD rats identified a panel of dysregulated miRNAs, among which miR-338-3p was the most prominently upregulated and was further corroborated by elevated miR-338-3p levels in serum samples from patients with RRD. Dual-luciferase reporter assays demonstrated that pleiotrophin (PTN) is a direct target of miR-338-3p. Functional studies showed that miR-338-3p overexpression in HaCaT and WS1 cells significantly enhanced apoptotic cell death and exacerbated radiation recall-associated cellular injury, whereas miR-338-3p inhibition attenuated apoptosis and promoted cellular recovery. In vivo, pharmacological or genetic inhibition of miR-338-3p, as well as activation of PTN, significantly alleviated the severity of RRLD. Enrichment analyses indicated that miR-338-3p-mediated suppression of PTN resulted in downregulation of the PI3K/Akt/Bcl2 signaling pathway, thereby compromising pro-survival signaling cascades. Consistently, rescue experiments using an Akt activator (SC79) partially restored p-Akt and Bcl2 expression and markedly reduced apoptotic responses, supporting the functional relevance of this pathway in RRLD. Collectively, these findings indicate that miR-338-3p acts as a critical epigenetic regulator of RRLD through modulation of the PTN/PI3K/Akt/Bcl2 axis and suggest that this molecular circuit represents a promising therapeutic target for mitigating clinical radiation recall-associated skin injury.