1271-OR: Long Noncoding RNA SNHG6 Reduces Cytokine-Induced Human β-Cell Immunogenicity and Death

Introduction and Objective: Type 1 diabetes (T1D) is driven by loss of immune tolerance and immune-mediated destruction of functional β cells. Effective therapies should preserve and regenerate β cells while reducing immunogenicity and restoring immune regulation. Harmine (H) plus exendin-4 (E) robustly expands human β cells, but its impact on β cell survival and immunogenicity under T1D-relevant inflammation is unknown. Here, we tested H+E effects on human β cell survival and cytokine-induced immunogenic programs, and the role of the downstream target long non-coding RNA SNHG6 (small nucleolar RNA host gene 6) on these effects. Methods: We used scRNA-seq, immunolabeling, qPCR, ELISA, flow cytometry and SNHG6 overexpression (OE) or knockdown (KD) on human β cells exposed to cytokines±H±E. Results: H+E reduced cytokine-induced human β cell death. scRNA-seq of cytokine-treated human islets showed H+E markedly decreased β cell inflammatory response genes. Comparison of differentially expressed genes across treatments identified 64 uniquely expressed genes after cytokines+H+E treatment. Among these, SNHG6 emerged as a top gene suppressed by cytokines and upregulated by H+E. HPAP human islet scRNA-seq data showed increased SNHG6 in surviving β cells in T1D. SNHG6 OE reduced human β cell death, preserved β cell identity (INS, MAFA, PDX1, GLUT2) and reduced apoptotic markers (TXNIP, CASP3), immunogenic and inflammatory mediators (HLA-B, CXCL10) and ER stress genes (CHOP, IRE1) after cytokine treatment. SNHG6 OE reduced cytokine-induced proinsulin secretion and restored glucose-stimulated insulin secretion, similarly to H+E. Conversely, SNHG6 KD blunted H+E-mediated human β cell protection, reduced β cell identity and enhanced inflammatory gene expression. Conclusion: H+E protects human β cells from cytokine-induced injury and limits inflammatory and immunogenic remodeling via SNHG6-centered pathways, highlighting SNHG6 as a potential therapeutic target to reduce immunogenicity and preserve functional β cells in T1D. Disclosure G. Lu: None. R.B. Kang: None. J. Aldaco: None. M. Varela: None. E. Oh: None. A. Stewart: Advisory Panel; Current; PaulexBio. D. Thurmond: None. A. Garcia-Ocana: Advisory Panel; Current; Paulex Bio.