Heat shock protein 27 in radiation-induced trismus: mechanistic insights and a hypothesis-generating framework

Abstract

Radiation-induced trismus (RIT) is a common and function-limiting late complication of radiotherapy for head and neck cancers, particularly when the masticatory muscles and temporomandibular joint receive high doses. Despite advances in intensity-modulated radiotherapy, RIT remains a significant survivorship problem, and robust biological biomarkers capable of predicting individual susceptibility are lacking. Heat shock protein 27 (HSP27; HSPB1) is a small heat shock protein that regulates multiple cellular stress responses, including proteostasis, cytoskeletal dynamics, redox homeostasis, apoptosis, and inflammatory signaling. In head and neck malignancies, HSP27 overexpression has been associated with treatment resistance and fibrosis-prone tissue remodeling. Experimental studies further demonstrate that HSP27 promotes transforming growth factor-β-mediated myofibroblast differentiation and extracellular matrix deposition, whereas pharmacologic or genetic inhibition attenuates radiation- or bleomycin-induced pulmonary fibrosis in vivo. Evidence from skeletal muscle biology also indicates that HSP27 modulates muscle integrity, denervation-associated atrophy, inflammatory signaling, and cytoskeletal stability. Although HSP27 has been widely investigated in radiation responses, fibrosis, and skeletal muscle stress adaptation, its potential involvement in the pathogenesis of RIT has not been systematically examined. This review proposes a conceptual framework in which HSP27 functions as an integrative molecular mediator linking radiation-induced oxidative stress, endothelial injury, and fibro-atrophic remodeling within the masticatory apparatus. By integrating current evidence on the epidemiology, dosimetric determinants, imaging correlates, and pathophysiology of RIT with the structural and functional biology of HSP27, this review provides the first tissue-specific synthesis of molecular stress signaling and clinical mechanisms relevant to RIT susceptibility. We further suggest that HSP27 signaling may influence susceptibility to fibro-neuromuscular injury in irradiated masticatory tissues. Given the absence of direct experimental or clinical evidence in this setting, these considerations are derived from mechanistic convergence across related biological systems and should be interpreted as biologically plausible but unproven, with potential implications for future biomarker development and biologically informed prevention strategies.