Identification of the critical immune-related drivers shared by non-alcoholic fatty liver disease and osteoporosis

Non-alcoholic fatty liver disease (NAFLD) and osteoporosis (OP) are two closely linked diseases, with immune cell dysregulation as a pivotal shared cause. However, the key drivers behind their pathogenesis remain poorly understood. Mendelian randomization studies were performed to identify immune-related risk and protective factors for NAFLD and OP, focusing on 731 immune cell traits and 91 circulating inflammatory proteins. Transcriptomic datasets associated with NAFLD and OP were obtained from the Gene Expression Omnibus database, and their consistency and representativeness were assessed through differential gene expression and functional enrichment analyses. ImmuCellAI was then utilized to profile immunocyte abundance and immune-related hub genes were identified via a protein-protein interaction network of common differentially expressed genes in NAFLD and OP. Furthermore, the clinical relevance and main sources of immune-related hub genes were explored using UK Biobank data and single-cell RNA sequencing (scRNA-seq) data. Finally, a high-fat diet (HFD)-induced mouse model was established to validate the bioinformatics findings. We identified 27 and 48 immune phenotypes that had causal effects on NAFLD and OP, respectively, showing similar immunopathogenic backgrounds. Differentially expressed genes maintained high consistency in each disease dataset and were significantly related to disease-specific functions and immune responses, such as inflammation and cytokine signaling. Subsequently, the dysregulation of T-helper (Th) cells was observed in both NAFLD and OP. Notably, three C-X-C motif chemokine ligand (CXCL) family genes, namely CXCL9, CXCL10, and CXCL11, were identified as hub genes, strongly correlating with Th cells. Furthermore, these CXCL family genes showed good diagnostic and predictive efficacy and were mainly expressed in myeloid cells. In the HFD-induced mouse model, the expression levels of these CXCL family hub genes were increased in both livers and bones, alongside elevated proportions of Th1, Th2, and Th17 cells. Our research unveils that the infiltration of immune cells plays a pivotal role in NAFLD and OP, and the interaction between CXCL9/10/11 and Th cells may serve as a shared mechanism underlying the pathogenesis of NAFLD and OP. This finding enhances our understanding of comorbidity mechanisms and presents novel selections for biomarker and therapeutic targets.