From chronic gastritis to gastric cancer: Mendelian randomisation and multi-omics interrogation of leukaemia inhibitory factor receptor (LIFR), hepatocyte growth factor (HGF), serine protease inhibitor E1 (SERPINE1) and interleukin-10 receptor subunit beta (IL10RB).

The inflammatory pathogenesis of chronic gastritis is well established, but the specific inflammatory factors that causally drive its progression to gastric cancer (GC) remain unclear. Here, we combined Mendelian randomisation (MR) with multi-omics analyses to identify key macromolecular mediators in this transition. Genome-wide association study datasets of chronic gastritis and GC were interrogated using two-sample MR for 91 inflammatory factors and 731 immune-cell traits, with inverse-variance-weighted MR as the primary method. Transcriptomic, proteomic and single-cell RNA sequencing data from The Cancer Genome Atlas, Gene Expression Omnibus and independent cohorts were integrated to delineate expression dynamics and immune-microenvironment remodelling across disease stages. Leukaemia inhibitory factor receptor (LIFR), hepatocyte growth factor (HGF) and serine protease inhibitor E1 (SERPINE1), interleukin-10 receptor subunit beta (IL10RB) emerged as core progression-associated macromolecules and were validated by quantitative reverse-transcription PCR, western blotting, immunohistochemistry and functional proliferation assays. Structure-based virtual screening and molecular docking identified three approved compounds with targeting potential: rofecoxib, used here as a chemical probe to validate LIFR rather than as a therapeutic candidate and predicted to functionally suppress HGF signalling; nabumetone, a putative SERPINE1 inhibitor; and N-acetyl-L-cysteine, which enhanced IL10RB expression. Collectively, these data define a molecular continuum from chronic gastritis to GC and highlight LIFR, IL10RB, SERPINE1 and HGF as pivotal biological macromolecules and candidate therapeutic targets. The repurposing potential of anti-inflammatory agents, particularly rofecoxib and nabumetone, suggests a feasible strategy to intercept the gastritis-carcinoma sequence.