GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324575/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324575GEOGSEfalseEngineering the insulin signal peptide to protect human pancreatic beta cells from autoimmune destructionThe autoreactive T cells that destroy beta cells in type 1 diabetes are largely targeting insulin signal peptide fragments. HLA knockout beta-cells have been proposed to create hypo-immune cells, but this strategy poses significant tumorigenic risks. As an alternative, we hypothesized that insulin signal peptide modification would give rise to beta-cells evading autoimmune recognition while maintaining insulin functionality. Here, we developed human beta-cell lines lacking endogenous insulin that we complemented with insulin carrying signal peptides from different hormones including chromogranin-A. We evaluated insulin synthesis, processing, secretion, activity, and immune evasion. Chromogranin-A signal peptide substitution directed insulin expression, maturation and secretion, maintaining physiological proinsulin/insulin ratios. Secreted insulin remained functional. Crucially, beta-cells expressing insulin with chromogranin-A signal peptide evaded recognition and killing by autoreactive T cells without inducing ER stress or compromising cellular identity. This approach may offer a targeted alternative to systemic immunosuppression to be used in stem-cell-derived therapies by engineering endogenous insulin locus.2026/08/13GSE324575GSM9579649GSM9579647GSM9579648GSM9579645GSM9579646GSM957964418573324575Homo sapiens