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

Oxaliplatin (OXA) induced a senescent phenotype in gastric cancer cells characterized by multiple senescence markers.

• Senescence was assessed by senescence-associated β-galactosidase (SA-β-Gal) staining, western blotting, immunofluorescence, and RT-qPCR
• OXA treatment resulted in p21 upregulation, positive SA-β-Gal staining, cell cycle arrest, and SASP secretion
• These findings collectively established that OXA induces a senescent phenotype in GC cells

Integrative multi-omics analysis identified NR4A1 as a central upstream regulator of OXA-induced senescence in gastric cancer cells.

• Multi-omics integration included transcriptomic, proteomic, and untargeted metabolomic analyses
• NR4A1 was identified as a key regulated gene in chemotherapy-induced senescence
• The PI3K/AKT pathway was found to be suppressed in OXA-induced senescence

NR4A1 expression was correlated with prognosis of patients with gastric cancer.

• Survival analysis was used to verify the clinical relevance of NR4A1 expression
• NR4A1 expression levels showed a statistically significant association with GC patient prognosis
• This finding suggests NR4A1 may serve as a prognostic biomarker in gastric cancer

NR4A1 knockdown attenuated OXA-induced senescence, restored PI3K/AKT activity, and reduced SASP expression in gastric cancer cells.

• Functional studies using NR4A1 knockdown demonstrated reduced senescence phenotype upon OXA treatment
• PI3K/AKT pathway activity was restored following NR4A1 knockdown
• SASP factor expression was reduced upon NR4A1 knockdown
• These results establish NR4A1 as a functional mediator of chemotherapy-induced senescence

OXA-induced senescence was associated with metabolic reprogramming including glycolysis enhancement and oxidative phosphorylation suppression.

• Metabolic alterations were identified through untargeted metabolomic profiling
• OXA-induced senescence was characterized by enhanced glycolysis and suppressed oxidative phosphorylation
• NR4A1 knockdown reversed these OXA-induced metabolic alterations
• These findings implicate the NR4A1/AKT-metabolism axis as a pivotal mechanism of therapy-induced senescence (TIS)

Therapy-induced senescence (TIS) is identified as a contributor to chemotherapy resistance and tumor progression in gastric cancer.

• Gastric cancer remains among cancers with extremely high morbidity and mortality rates worldwide
• Chemotherapy resistance limits the therapeutic efficacy of GC treatment
• TIS is described as 'vital for inducing chemotherapy resistance and promoting tumor progression'
• The authors propose 'one-two punch' approaches targeting senescent tumor cells as a novel therapeutic strategy