Ageing accelerates metastasis through increased EMT and unfolded protein response signaling, with ATF4 acting as a central transcriptional hub whose activity is amplified by ageing.

Overall, ageing activates the PERK–ATF4 arm of the ISR, driving metastatic progression in lung cancer by promoting EMT and metabolic rewiring, and suggesting that inhibiting the ATF4/GLS axis could be a therapeutic strategy.

In human LUAD models, ATF4 overexpression raises metastatic traits, indicating potential translational relevance for targeting the ATF4–ISR–GLS axis in age-related metastasis.

ATF4 controls sensitivity to GLS inhibitors; blocking GLS or ATF4 diminishes metastatic capabilities, and rescue experiments show dependence on alpha-ketoglutarate and glutamate availability.

In KP mouse models, older mice exhibit fewer primary lung tumors but markedly more metastasis and faster disease progression compared with younger counterparts.

Genetic or pharmacological inhibition of ATF4 (via CRISPR knockdown or ISRIB) reduces metastasis in KP-O cultures, while ATF4 overexpression in KP-Y cultures heightens metastasis and strengthens EMT and UPR pathway activity.

Metabolic reprogramming accompanies ATF4-driven metastasis: KP-O cells show heightened glycolysis and glutamine-driven anaplerosis, with GLS-mediated glutaminolysis becoming essential for metastatic spread.