HSP27 in autoimmune diseases: Context-dependent regulation and clinical potential

Heat shock protein 27 (HSP27) is a crucial member of the small heat shock protein family with a molecular weight of approximately 27 kDa, playing key roles in cellular stress response, protein homeostasis, and cell survival regulation. Recent studies have revealed that HSP27 plays a complex dual role in the pathogenesis of autoimmune diseases, which we define as the "HSP27 Dual Regulatory Paradox." Aim To systematically review the bidirectional immunomodulatory mechanisms of HSP27 in autoimmune diseases and to evaluate its clinical potential as a disease biomarker and therapeutic target, based on a "cell type-microenvironment-disease stage" three-dimensional regulatory model.

A comprehensive literature review was conducted using PubMed and other databases up to 2025, focusing on the structural characteristics, biological functions, and immunoregulatory roles of HSP27 in typical autoimmune diseases including Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Behçet's disease, psoriasis, myasthenia gravis, systemic sclerosis, type 1 diabetes, and inflammatory bowel disease.

HSP27 exhibits a context-dependent dual regulatory role: in structural cells such as synovial fibroblasts, it acts as an essential component of the TAK1-p38 MAPK-MK2 signaling pathway, promoting pro-inflammatory mediators (IL-6, IL-8); in the monocyte-macrophage system, it induces IL-10 secretion and limits IL-1β release. Anti-HSP27 antibody positivity reaches 72% in rheumatoid arthritis and 57% in Behçet's disease patients. HSP27 expression correlates with disease activity across multiple autoimmune conditions and shows disease-specific patterns: neuroprotective in multiple sclerosis, anti-apoptotic in lupus nephritis, and pro-inflammatory in rheumatoid synovium. HSP27-targeted therapeutic strategies, including small-molecule inhibitors (OGX-427, RP101, J2), antisense oligonucleotides, and HSP-based immune tolerance induction, are under preclinical and clinical evaluation.

HSP27 represents a multifaceted molecular target in autoimmune diseases, with its function determined by the interplay of cell type, microenvironment, and disease stage. A thorough understanding of this three-dimensional regulatory model will provide an important theoretical basis for developing novel diagnostic markers and precision-targeted therapeutic strategies. Future studies integrating single-cell sequencing, spatial omics, and large-scale clinical cohorts are needed to translate HSP27 biology into clinical applications.