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BackgroundMalignant neoplasms of bone and articular cartilage represent a rare group of highly invasive tumours with a poor prognosis, whose molecular mechanisms remain incompletely understood. Systematic identification of potential pathogenic proteins holds significance for early diagnosis and targeted therapy.MethodsA genetic tool was constructed using nine large-scale cis-protein quantitative trait loci (pQTL) datasets. Dual-sample Mendelian randomisation analysis was performed with plasma proteins as exposure and malignant neoplasms of bone and articular cartilage risk as the outcome. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on proteins showing suggestive causal associations (p < 0.05). Sensitivity analyses, Steiger's directionality tests and co-localisation studies were conducted on Bonferroni-corrected significant proteins. Finally, candidate small-molecule drugs were predicted using the Enrichr database and molecular docking analysis.ResultsPreliminary Mendelian randomisation analysis identified 171 suggestive causal proteins, with 80 positively and 91 negatively correlated with the risk of malignant neoplasms of bone and articular cartilage. Enrichment analysis revealed that these proteins primarily participated in immune regulation, extracellular matrix degradation and proteolysis-related pathways. Following Bonferroni correction, seven proteins-GNLY, PCSK7, ADAMTS5, PDCD1LG2, SCG3, CXCL16 and CNTN1-retained significant causal associations. Further co-localisation analysis revealed that ADAMTS5, GNLY and PCSK7 shared genetic variants associated with the risk of malignant neoplasms of bone and articular cartilage. Molecular docking analysis indicated that compounds such as aspirin and vitamin E exhibited low binding energies with GNLY, PCSK7 and ADAMTS5, suggesting potential therapeutic intervention opportunities.ConclusionThis study identified three proteins (GNLY, PCSK7 and ADAMTS5) associated with a high risk of malignant neoplasms of bone and articular cartilage through Mendelian randomisation and co-localisation analyses, providing novel molecular evidence for early diagnosis, risk assessment and potential targeted therapies for malignant neoplasms of bone and articular cartilage.