ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
Syntaxin 4 (STX4) protects islet b-cells from cytokine-induced senescence
Miwon Ahn 1
Sneha Susan Varghese 1
Erika McCown 1
Supriyo Bhattacharya 1
Katarzyna Dabrowska 1
Nathaniel Hansen 1,2
Patrick Pirrotte 1,2
Debbie C Thurmond 1
Sangeeta Dhawan 1
1. City of Hope National Medical Center, Duarte, United States
2. Translational Genomics Research Institute, Phoenix, United States
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Abstract
Abstract Type 1 diabetes (T1D) is characterized by progressive loss of pancreatic β-cell function, which is accelerated by cytokine-induced senescence and the accompanying senescence-associated secretory phenotype (SASP). Here, we identify Syntaxin 4 (STX4), a t-SNARE protein previously recognized for its cytoprotective properties, as a key regulator that mitigates β-cell senescence under diabetogenic stress. β-cell-specific overexpression of STX4 in MIN6 cells, human islets, and murine islets exposed to cytokines markedly reduced the accumulation of senescence markers p21 and γH2AX. In non-obese diabetic (NOD) mice, induced STX4 expression reduced p21 and γH2AX accumulation and preserved nuclear Lamin B1 expression in pancreatic islets, supporting its in vivo senoprotective effect. Integrated single-cell RNA sequencing and conditioned medium proteomics revealed that STX4 represses senescence-related transcriptional programs and reshapes the β-cell secretome by enriching proteins involved in purine ribonucleotide metabolism. Collectively, our findings suggest that STX4 protects β cells from cytokine-induced senescence, highlighting its potential as a therapeutic modulator to preserve functional β-cell mass in T1D.
Summary
Keywords
b-cell senescence, Inflammation, senescence-associated secretory phenotype (SASP), Syntaxin 4, type 1 diabetes
Received
14 October 2025
Accepted
19 February 2026
Copyright
© 2026 Ahn, Varghese, McCown, Bhattacharya, Dabrowska, Hansen, Pirrotte, Thurmond and Dhawan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Debbie C Thurmond; Sangeeta Dhawan
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