LINP1 suppresses radiation-induced cellular senescence in keratinocytes by modulating the mTOR-p53 axis.

Radiation-induced skin injury (RISI) represents a significant clinical challenge in radiotherapy, owing to its high incidence and role in limiting therapeutic doses. Cellular senescence is a critical driver of RISI pathogenesis. Here, we identify LINP1 as a markedly upregulated lncRNA following ionizing radiation (IR), and functional assays indicates that LINP1 promotes cell survival and limites radiation-induced DNA damage accumulation. Mechanistically, LINP1 attenuates radiation-induced cellular senescence through modulation of the mTOR-p53 signaling axis. Specifically, LINP1 associates with the FAT domain of mTOR via a central nucleotide region termed the mTOR-binding domain (MBD) and attenuates the interaction between mTOR and p53, thereby reducing p53 Ser15 phosphorylation and downstream senescence-associated signaling. Validation in ex vivo human skin explants demonstrates that LINP1 depletion exacerbates radiation-induced tissue damage, persistent DNA damage accumulation, and senescence-associated phenotypes, supporting its physiological relevance in native human tissue. Collectively, our study not only identifies LINP1 as a key radioprotective lncRNA that regulates radiation-induced senescence through the mTOR-p53 axis, but also provides new mechanistic insights and a conceptual basis for future development of RNA-based radioprotective strategies.