Linalool targets NR3C2 to inhibit NF-κB-mediated gastric cancer progression

Gastric cancer (GC) is a major global health challenge. This study explores the efficacy of linalool in GC and further elucidates its underlying mechanisms. Linalool inhibited the proliferation, migration, and invasion of GC cells and prevented transplanted tumor growth in nude mice. Linalool directly interacted with and stabilized the NR3C2 protein, inhibiting its proteasomal degradation. Functional rescue experiments demonstrated that knockdown of NR3C2 partially reversed the antitumor effects of linalool. Further studies revealed that NR3C2 transcriptionally activated NFKBIZ and inhibited NF-κB signaling, and restoring NFKBIZ expression reversed GC progression caused by NR3C2 deficiency. In clinical samples, the expression levels of NR3C2 and NFKBIZ were lower in GC tissues than in adjacent normal tissues, and the two markers were positively correlated in the tumor tissues. Furthermore, low expression of both NR3C2 and NFKBIZ was significantly associated with higher T stages and more advanced pTNM stages and was accompanied by NF-κB signaling activation and elevated levels of inflammatory cytokines in tumor tissues. Overall, linalool inhibits GC progression by upregulating NR3C2 and transcriptionally activating NFKBIZ, thereby suppressing NF-κB signaling. Low NR3C2/NFKBIZ expression is associated with adverse clinical and pathological features in GC.