Hsp90 as a master regulator in autoimmunity: from cellular stress to clinical opportunity

Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that governs the folding, stabilization and activity of a wide range of client proteins, many of which are critical regulators of immune cell signalling and inflammatory responses. Recent research has underscored the role of Hsp90 in orchestrating both innate and adaptive immune functions, particularly in the context of autoimmune diseases. In autoimmune diseases, dysregulated immune pathways often involve Hsp90-dependent client proteins, including key kinases and transcription factors. By modulating the activation, differentiation and survival of immune cells Hsp90 emerges as a central node in autoimmune pathogenesis. Importantly, the pharmacological inhibition of Hsp90 has shown promise in preclinical models of autoimmunity, where it attenuates pro-inflammatory pathways. In this review, we examine the immunoregulatory functions of Hsp90 with a focus on autoimmune disorders, highlighting its role in disease-driving pathways, such as Nuclear Factor Kappa B (NF-κB), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) and Mitogen-Activated Protein Kinase (MAPK). We also discuss the current landscape of Hsp90 inhibitors, their mechanism of action, and emerging data on their efficacy in autoimmune disease models. Understanding how Hsp90 shapes immune cell behaviour and inflammation provides a compelling framework for its development as a novel therapeutic target in chronic autoimmune conditions.