NR4A1 mediates chemotherapy‑induced senescence via the PI3K/AKT pathway in gastric cancer cells.

Gastric cancer (GC) remains among the cancers with extremely high morbidity and mortality rates worldwide, and chemotherapy resistance limits its therapeutic efficacy. Therapy‑induced senescence (TIS) is vital for inducing chemotherapy resistance and promoting tumor progression, highlighting the need to explore its regulatory mechanisms. To investigate oxaliplatin (OXA)‑induced senescence in GC cells, cellular senescence was assessed by senescence‑associated β‑galactosidase (SA‑β‑Gal) staining, western blotting, immunofluorescence, and reverse transcription‑quantitative polymerase chain reaction for the senescence‑associated secretory phenotype (SASP) factors. Moreover, multi‑omics integration including transcriptomic, proteomic and untargeted metabolomic, was used to identify key regulators and pathways. OXA induced a senescent phenotype characterized by p21 upregulation, SA‑β‑Gal staining, cell cycle arrest and SASP secretion. Integrative multi‑omics analysis revealed that NR4A1 is a central upstream regulator, and the PI3K/AKT pathway is suppressed in OXA‑induced senescence. Notably, survival analysis verified that NR4A1 expression was correlated with the prognosis of patients in GC. Functional studies demonstrated that NR4A1 knockdown attenuated OXA‑induced senescence, restored PI3K/AKT activity, and reduced SASP expression. Metabolomic profiling revealed that OXA‑induced senescence induced metabolic reprogramming, including glycolysis enhancement and oxidative phosphorylation suppression. Notably, NR4A1 knockdown reversed these metabolic alterations. The present study identified NR4A1 as a key regulated gene in chemotherapy‑induced senescence in GC and verified that the NR4A1/AKT‑metabolism axis is vital for the pivotal mechanism of TIS. These findings may provide a novel therapeutic strategy to optimize chemotherapy and develop 'one‑two punch' approaches targeting senescent tumor cells.