Zhang Bingwei, Fan Yumei, Tan Ke
Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China.
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Int J Biol Sci. 2025 Apr 28;21(8):3351-3378. doi: 10.7150/ijbs.110447. eCollection 2025.
The heat shock factor 1 (HSF1) is a master transcription regulator that orchestrates the expression of heat shock proteins (HSPs) in response to various cellular stresses. Dysfunction of HSF1 contributes to the pathogenesis of a spectrum of acute and chronic diseases, including cancer. Consequently, the modulation of HSF1 activity through the development of small molecules emerges as a promising therapeutic strategy for disease treatment. The activation of HSF1 is a multifaceted process, governed by a complex interplay of regulatory mechanisms, including post-translational modifications, protein-protein interactions, and a balance between its activation and inactivation. Recently, a plethora of compounds, ranging from synthetic to naturally derived, that either inhibit or activate HSF1 was identified, holding considerable potential for the treatment of numerous human diseases. In this comprehensive review, we elucidate the sophisticated mechanisms underlying activation of human HSF1, introduce its role in the etiology of diseases, and provide a comprehensive summary of the inhibitors and activators of HSF1 that have been discovered to date. This review not only offers novel insights for the development of small molecule therapeutics targeting HSF1 but also charts new territories in the design of innovative interventions for the amelioration of disease.
热休克因子1（HSF1）是一种主要的转录调节因子，可协调热休克蛋白（HSPs）的表达以应对各种细胞应激。HSF1功能障碍促成了包括癌症在内的一系列急慢性疾病的发病机制。因此，通过开发小分子来调节HSF1活性成为一种很有前景的疾病治疗策略。HSF1的激活是一个多方面的过程，受包括翻译后修饰、蛋白质-蛋白质相互作用以及其激活与失活之间平衡等调节机制的复杂相互作用所支配。最近，人们鉴定出了大量从合成到天然衍生的、可抑制或激活HSF1的化合物，它们在治疗多种人类疾病方面具有巨大潜力。在这篇全面的综述中，我们阐明了人类HSF1激活背后的复杂机制，介绍了其在疾病病因学中的作用，并对迄今为止发现的HSF1抑制剂和激活剂进行了全面总结。这篇综述不仅为开发靶向HSF1的小分子疗法提供了新见解，还为设计改善疾病的创新干预措施开辟了新领域。
