Crosstalk Between the NRF2 Signaling Pathway and Heat Shock Proteins: Implications for Cellular Stress Response and Disease Therapy.

Cells are continuously exposed to oxidative and proteotoxic stress that disrupt redox balance and protein homeostasis. Two major cytoprotective systems-the nuclear factor erythroid 2-related factor 2 (NRF2) pathway and the heat shock response (HSR) mediated by heat shock factor 1 (HSF1) and heat shock proteins (HSPs)-form an interconnected stress-adaptation network that coordinates redox defense, proteostasis, and cellular survival. Although historically viewed as largely independent pathways, accumulating evidence demonstrates extensive bidirectional and context-dependent crosstalk through transcriptional coregulation, protein-protein interactions, posttranslational mechanisms, and shared molecular hubs, including p62/SQSTM1 and the ubiquitin-proteasome system. This network integrates antioxidant defense with protein quality control, mitochondrial homeostasis, and inflammatory and metabolic signaling; however, NRF2 and HSR responses can also become functionally uncoupled under specific biochemical and metabolic conditions. This review critically examines the molecular mechanisms underlying NRF2-HSP crosstalk and its functional consequences in neurodegeneration, cancer, ischemia-reperfusion (I/R) injury, aging, and tumor immunity. Particular attention is given to the dual role of this axis: transient activation promotes cytoprotection, proteostasis, and tissue recovery, whereas chronic or constitutive activation can support tumor metabolism, immune evasion, and therapeutic resistance. In I/R injury, endoplasmic reticulum (ER) stress (ERS)-induced XBP1-HRD1 signaling may impose an additional constraint on NRF2 activity, highlighting an important limitation of endogenous cytoprotection. Finally, we discuss therapeutic strategies targeting NRF2, HSF1, and HSPs, emphasizing the challenges of systemic pathway modulation, the importance of pharmacodynamic biomarkers and molecular stratification, and the potential of rational combination approaches. A context-, tissue-, and cell-specific understanding of NRF2-HSP signaling will be essential for translating this complex stress-response network into precision therapeutic strategies.