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Two major cytoprotective systems\u2014the nuclear factor erythroid 2\u2013related factor 2 (NRF2) pathway and the heat shock response (HSR) mediated by heat shock factor 1 (HSF1) and heat shock proteins (HSPs)\u2014form an interconnected stress\u2010adaptation network that coordinates redox defense, proteostasis, and cellular survival. Although historically viewed as largely independent pathways, accumulating evidence demonstrates extensive bidirectional and context\u2010dependent crosstalk through transcriptional coregulation, protein\u2013protein interactions, posttranslational mechanisms, and shared molecular hubs, including p62\/SQSTM1 and the ubiquitin\u2013proteasome 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\u2013HSP crosstalk and its functional consequences in neurodegeneration, cancer, ischemia\u2013reperfusion (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)\u2010induced XBP1\u2013HRD1 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\u2010, tissue\u2010, and cell\u2010specific understanding of NRF2\u2013HSP signaling will be essential for translating this complex stress\u2010response network into precision therapeutic strategies.<\/jats:p>","DOI":"10.1155\/omcl\/8809922","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T08:07:11Z","timestamp":1791792431000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Crosstalk Between the NRF2 Signaling Pathway and Heat Shock Proteins: Implications for Cellular Stress Response and Disease Therapy"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1058-8778","authenticated-orcid":false,"given":"Milad","family":"Faraji","sequence":"first","affiliation":[{"name":"Department of Basic Sciences School of Veterinary Medicine Shiraz University  Shiraz Iran  shirazu.ac.ir"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5501-1028","authenticated-orcid":false,"given":"Saeed","family":"Nazifi","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences School of Veterinary Medicine Shiraz University  Shiraz Iran  shirazu.ac.ir"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom15010113"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11122345"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.2c00131"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2024.12.010"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.11.024"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6943"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.8.4184"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.46.120604.141046"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.24.10941-10953.2004"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2022.12.003"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.172398899"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20150568"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-021-03070-8"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2017.08.002"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R500010200"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11262-5"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.003376"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049258"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11050829"},{"key":"e_1_2_12_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12192-022-01253-5"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13070758"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12071371"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/7469326"},{"key":"e_1_2_12_24_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.43.100901.140229"},{"key":"e_1_2_12_25_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7342"},{"key":"e_1_2_12_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/ame2.70017"},{"key":"e_1_2_12_27_2","doi-asserted-by":"publisher","DOI":"10.1155\/bmri\/9266092"},{"key":"e_1_2_12_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.70013"},{"key":"e_1_2_12_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02100-6"},{"key":"e_1_2_12_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48045-2"},{"key":"e_1_2_12_31_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14194702"},{"key":"e_1_2_12_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.16.7130-7139.2004"},{"key":"e_1_2_12_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00764-20"},{"key":"e_1_2_12_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2018.06.013"},{"key":"e_1_2_12_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1332049"},{"key":"e_1_2_12_36_2","volume-title":"Activation of the Proteasome Machinery by NRF2\/Mutant p53 Axis and Its Therapeutic Implications for Triple Negative Breast Cancer","author":"Lisek K. 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