Autoimmune diseases, including type 1 diabetes (T1D), rheumatoid arthritis (RA), multiple sclerosis (MS) and Hashimoto's disease (HT), affect more than 5% of the population across various regions [1]. While these diseases target different tissues, they share several common features, including significant genetic overlap, chronic local inflammation and similar mechanisms of target tissue damage [1,2]. Common degenerative diseases, such as type 2 diabetes (T2D) and Alzheimer's disease (AD), also have inflammatory components, though their autoimmune involvement remains unclear [[3], [4], [5], [6]]. Despite these shared features, autoimmune diseases are typically studied independently, with emphasis on immune dysfunction rather than intrinsic signalling within the target tissues. However, growing evidence suggests that target tissues contribute to their own destruction by engaging in a harmful crosstalk with the immune system [7,8], a process amplified by inflammatory mediators that alter RNA and protein expression and exacerbate autoimmune responses [9]. The rationale for selecting the diseases for the present study, namely T1D, RA, MS, HT, T2D and AD, includes: 1. Pancreatic β-cells and thyroid follicular cells are specialized hormone producing cells that may share intrinsic molecular traits; 2. β-cells and neurons exhibit similarity in gene expression, particularly in the regulation of specific splicing factors and splice variants [10,11]; 3. T1D, RA and MS share several candidate genes in common and exhibit, to some extent, similar upregulated inflammatory pathways at the target tissue level [7]; 4. Inflammation and amyloid deposition are involved in both T2D and AD [5,6]; 5. Therapeutic goals across T1D, MS and, to some extent, T2D and AD, include reducing local inflammation, decrease apoptosis of the target tissues and, in more advanced stages of disease, regenerate lost β-cells or neurons; 6. The fact that RA is, at least in part, a tissue-targeted autoimmune disease, involving infiltration of T- and B-cells [12] and shares several gene expression pathways with T1D at the target tissue level [7]. Across these diseases, upregulation of pathways related to antigen presentation, apoptosis and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling are frequently observed in affected tissues [7,[13], [14], [15]]. Identifying core pathogenic pathways shared among diseases could reveal targets for therapy and drug repurposing, moving beyond disease-specific approaches. Of note, many of the recently approved or investigational drugs for autoimmune diseases target broad inflammatory signalling pathways (e.g. JAK-STAT), instead of single disease-specific targets [16,17].

T1D is characterized by the autoimmune destruction of pancreatic β-cells, primarily mediated by cytotoxic CD8+ T-cells that recognize β-cell–derived antigenic peptides. Several T1D risk genes acts directly within β-cells, influencing their susceptibility to viral infections [18], interactions with the immune system and apoptosis pathways [19,20]. In T1D, β-cells upregulate MHC class I genes and proteins (e.g., HLA-A, HLA-B, HLA-C) [21,22], suggesting that β-cells themselves may actively present neoantigens to CD8+ T-cells and thus contribute to their immune-mediated destruction. Simultaneously, β-cells in T1D also express immune-regulatory molecules such as programed cell death ligand 1 (PDL1) and HLA-E, indicating potential endogenous mechanisms of defense [19,23,24]. Although insulin therapy remains the cornerstone of T1D management, it does not prevent long-term complications or reduce the risk of early mortality [25]. Preserving residual β-cell function after diagnosis has been linked to better clinical outcomes, including reduced insulin requirements and lower risk of severe hypoglycemia events and vascular complications [16,26,27]. Immune-targeted therapies alone cannot prevent T1D, underscoring the need for protective β-cell targeted strategies to block their deleterious dialog with the immune system and prevent progressive cell loss [30].

In this study we performed transcriptome comparisons between the target tissues of six diseases to identify common pathogenic gene signatures and leveraging them to repurpose small-molecule compounds for the treatment of T1D. Our transcriptomic analysis revealed that T1D exhibits different degrees of gene expression similarities at the target tissue level with all these diseases, with the highest resemblance to HT. Single-cell RNA-seq (scRNA-seq) analysis of T1D donors confirmed these inflammatory responses in pancreatic β-cells. Using Connectivity Map analyses [31] for these key common genes, we identified potential therapeutic candidates and experimentally validated one of them, fibroblast growth factor receptor 1 (FGFR1) inhibitor, demonstrating its ability to protect human β-cells from immune mediated damage, highlighting its potential relevance in T1D therapy.