SRRM3 is an RNA-binding protein that functions as a master regulator of tissue-specific microexon splicing programs, with primary roles in pancreatic islet function and neuronal development. In pancreatic beta cells, SRRM3 regulates the inclusion of islet-specific microexons (IsletMICs) in genes controlling vesicle transport and exocytosis 1. SRRM3 expression is glucose-responsive, and its depletion leads to inappropriate insulin secretion and impaired glucose homeostasis 1. The mechanism involves fine-tuning protein function through precise microexon inclusion, with SRRM3 sensitivity determined by core splicing architecture and spliceosomal recruitment efficiency 2. In the nervous system, SRRM3 shares overlapping but distinct functions with its paralog SRRM4, together regulating microexon splicing in neuronal differentiation and GABAergic neurotransmission 3. While individual microexon deletions produce mild effects, simultaneous loss of SRRM3 and SRRM4 causes severe neurological phenotypes 4. Disease relevance includes genetic variants affecting SRRM3 expression associated with type 2 diabetes and fasting glucose variation 1, and dysregulation linked to pancreatic neuroendocrine tumors where SRRM3 upregulation promotes aberrant hormone secretion 5. Additionally, SRRM3 downregulation mediates tumor-suppressive effects in breast cancer through REST-003 regulation 6. SRRM3 represents a therapeutic target for metabolic and malignant diseases involving microexon misregulation 7.