ABSTRACT Autoimmune diseases exhibit strikingly increased prevalence in females (e.g. systemic lupus erythematosus [SLE], female-to-male ratio 9:1), whereas in contrast, infectious diseases affect more men than women. Despite its clinical impact, the molecular underpinnings of sex-biased immune regulation remain elusive. To address this knowledge gap, this project focuses on the immunometabolic function of VGLL3 (Vestigial Like Family Member 3), a female-increased, keratinocyte-expressed molecule known to promote both cutaneous and systemic autoimmunity. This project tests the hypothesis that VGLL3 coordinates female-biased metabolic stress response, whose hyperactivation causes autoimmunity by: Aim 1. Define the female-biased cellular stress response mediated by VGLL3. Aim 2. Determine the molecular mechanism by which metabolic stress potentiates VGLL3 induction by IFN. Aim 3. Establish the in vivo role of VGLL3-mediated stress response in autoimmune pathogenesis. With successful completion of the work proposed, we will have gained insights into the molecular basis underlying sexual dimorphism in immunity. By establishing the immunometabolic function of VGLL3, we will demonstrate the importance of maintaining metabolic homeostasis in combating autoimmunity, and provide a novel target and pathway for sex-specific prevention and treatment of immune-associated diseases.