Am J Physiol Endocrinol Metab. 2026 Jun 12. doi: 10.1152/ajpendo.00006.2026. Online ahead of print.
ABSTRACT
Activating transcription factor 3 (ATF3) functions as a central regulator of metabolic homeostasis across multiple physiological systems. A bibliometric analysis of ATF3 research (1993-2025) demonstrates an exponential growth trend, particularly in metabolic disease research demonstrating a robust 14.15% annual growth rate, underscoring ATF3's emerging importance in metabolic regulation. This review synthesizes current knowledge of ATF3's multisystem regulatory functions, spanning endocrine, cardiovascular, nervous, immune, respiratory, digestive, and urogenital systems, and explores the molecular mechanisms by which ATF3 coordinates cellular stress responses, metabolic adaptation, and tissue-specific homeostasis. Particular emphasis is placed on ATF3's regulation of perivascular adipose tissue (PVAT) and its contribution to obesity-related vascular dysfunction. Atf3 deficiency profoundly alters PVAT structure, adipocyte browning capacity, inflammatory signaling, and insulin sensitivity, establishing ATF3 as a critical determinant of adipose-vascular crosstalk. We further evaluate emerging therapeutic strategies targeting ATF3, including natural compounds (Salvia miltiorrhiza derivatives, sulfuretin) and synthetic modulators (SW20.1, ST32 series), that show promise in experimental metabolic disorders. Current challenges in therapeutic translation include achieving tissue-specific targeting and optimizing drug delivery systems. This comprehensive analysis positions ATF3 as a master regulator linking stress responses with metabolic homeostasis, highlighting its potential as a therapeutic target for obesity-related metabolic and vascular disorders.
PMID:42284073 | DOI:10.1152/ajpendo.00006.2026