ATMLP Enhances Radioresistance in Non-Small Cell Lung Cancer through AKT-Mediated Lipid Droplet Accumulation.

Radioresistance remains a critical barrier to successful radiotherapy in non-small cell lung cancer (NSCLC). ATMLP, a mitochondrial-localized peptide encoded by lncRNA AFAP1-AS1, has been previously associated with tumor progression. In this study, we uncover a previously unrecognized role of ATMLP in promoting radioresistance by facilitating intracellular lipid droplet (LD) accumulation through AKT pathway activation. Mechanistically, ATMLP reduces radiation-induced reactive oxygen species (ROS) accumulation, thereby relieving ROS-mediated suppression of AKT phosphorylation, which in turn enhances lipid storage and promotes tumor cell survival under ionizing radiation. Genetic knockout of ATMLP leads to excessive ROS generation, impaired AKT activation, and diminished LD accumulation, ultimately sensitizing NSCLC cells to radiation. Conversely, ATMLP overexpression decreases ROS levels, increases post-radiation clonogenicity, and accelerates tumor growth. Inhibition of the AKT pathway abrogates ATMLP-induced lipid accumulation and reverses the radioresistant phenotype. These findings identify ATMLP as a key mediator linking ROS homeostasis and lipid metabolic reprogramming to radiation response, and suggest that targeting the ATMLP-AKT axis may represent a promising therapeutic strategy to enhance radiotherapy efficacy in NSCLC.