Multi-Omics Characterization of ABHD12 Across Pan-Cancer and Validation of Its Role in Promoting Proliferation and Metastasis in Breast Cancer

Jiawei Zhao,1,* Yuting Gou,1,* Yiyang Wang,1,* Yongxiang Li,1 Haotian Ma,1 Yiting Xing,2 Haohao Peng,2 Chenming Guo1,3 1Department of Breast Surgery, Center of Digestive and Vascular, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 2Department of Clinical Medicine, Xinjiang Medical University, Urumqi, People’s Republic of China; 3State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chenming Guo, Email gcm_xjmu@yeah.netPurpose: ABHD12 is linked to cancer and neurodegeneration; we systematically characterized its pan-cancer role and validated its oncogenic function in breast cancer (BRCA) to guide mechanistic studies.Methods: We integrated multi-omics data from TCGA, GTEx, and various public platforms to analyze expression, prognosis, genetic variations, methylation, immune infiltration, and drug resistance. In qRT-PCR, Western blot, functional assays (CCK-8, wound healing, colony formation), and a nude mouse xenograft model, were conducted to validate ABHD12’s role in BRCA.Results: ABHD12 was significantly upregulated at both mRNA and protein levels across multiple cancers. High expression correlated with poorer overall survival in BRCA, GBM, LGG, LIHC, and UVM. It demonstrated strong to moderate diagnostic value. ABHD12 expression was associated with copy number variations (CNVs) across 23 cancers, but not with methylation. It also correlated with immune cell infiltration (especially with macrophage), tumor mutational burden, neoantigens, microsatellite instability, and immune-related genes in certain cancers, and was potentially linked to resistance to multiple chemotherapeutics. KEGG analysis indicated that ABHD12 may play a potential role in the AMPK pathway. In BRCA, ABHD12 was higher in tumors than normal tissues. Functional studies showed ABHD12 enhanced proliferation, invasion, and migration, while silencing suppressed these traits. In vivo, ABHD12-overexpressing cells formed larger tumors, confirming its tumor-promoting role.Conclusion: ABHD12 may act as an oncogene across multiple cancers, linked to poor prognosis, diagnostic potential, chemotherapy resistance, and immunotherapy response. Its dysregulation is driven by CNVs rather than promoter methylation. ABHD12 might modulate macrophage polarization via the AMPK signaling pathway, leading to the remodeling of the tumor immune microenvironment. In vitro and vivo studies confirm its pro-tumorigenic role in BRCA, highlighting ABHD12 as a multifunctional biomarker and a molecular nexus linking lipid metabolism, immunity, and treatment resistance—warranting further study.Keywords: ABHD12, pan-cancer, prognosis, tumor immunity, drug resistance