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Heat shock response

The heat shock response (HSR) is an evolutionarily conserved cellular mechanism that protects cells and organisms from proteotoxic stress induced by environmental challenges such as elevated temperatures, oxidative damage, chemicals, and UV radiation, primarily through the rapid induction of heat shock proteins (HSPs) that maintain protein homeostasis.^[1] This response is activated when stressors cause protein misfolding or denaturation, leading to the transcriptional upregulation of HSP genes via heat shock factors (HSFs), which bind to specific heat shock elements in promoter regions to orchestrate a protective program that halts general protein synthesis while prioritizing chaperone production.^[1] HSPs, including families like HSP70, HSP90, and small HSPs, act as molecular chaperones to assist in refolding damaged proteins, target irreparable ones for degradation via the ubiquitin-proteasome system or autophagy, and prevent cytotoxic aggregation, thereby enhancing cellular resilience and thermotolerance.^[1] First observed in 1962 by Ferruccio Ritossa in Drosophila melanogaster salivary gland cells exposed to heat, the HSR has since been identified across all domains of life, from prokaryotes to eukaryotes, underscoring its fundamental role in survival under adverse conditions.^[1] In mammals, the primary regulator is HSF1, which exists in a monomeric, inactive form under normal conditions but trimerizes and translocates to the nucleus upon stress to drive HSP expression; this process is modulated by phosphorylation, sumoylation, and interactions with HSPs themselves, ensuring a tightly controlled response that adapts to stress intensity and duration.^[1] Beyond heat, the HSR integrates with other pathways, such as the unfolded protein response in the endoplasmic reticulum, to broadly safeguard proteostasis during infections, ischemia, or heavy metal exposure.^[2] The HSR's dysregulation is implicated in numerous human diseases, including neurodegeneration (e.g., Alzheimer's and Parkinson's, where impaired HSP function contributes to protein aggregates like amyloid-beta), cancer (where elevated HSPs promote tumor survival and resistance to therapy), and cardiovascular disorders, highlighting its therapeutic potential through HSP modulators or HSF1 inhibitors.^[1] In healthy contexts, the response supports immune function by influencing antigen presentation and cytokine signaling, while its evolutionary conservation—from bacterial DnaK systems to human HSP networks—reflects billions of years of adaptation to fluctuating environments.^[1] Ongoing research explores small-molecule activators of the HSR to combat aging-related proteotoxicity and enhance stress tolerance in clinical settings.^[2]

Overview

Definition and triggers

The heat shock response (HSR) is an evolutionarily conserved genetic program that enhances the expression of heat shock proteins (HSPs) to mitigate proteotoxic stress and maintain cellular proteostasis.^[1] This mechanism, first identified in Drosophila melanogaster through exposure to elevated temperatures, enables cells to counteract protein misfolding and aggregation by prioritizing the synthesis of molecular chaperones.^[3] Primary triggers of the HSR include elevated temperatures (heat shock), oxidative stress, heavy metals, hypoxia, and proteotoxic agents such as unfolded or denatured proteins.^[4] Heat shock directly causes protein denaturation, while oxidative stress and heavy metals like cadmium generate reactive oxygen species that damage proteins; hypoxia, in turn, impairs oxygen-dependent folding processes, leading to accumulation of misfolded polypeptides.^[5] These stressors activate the response by disrupting protein homeostasis, prompting a rapid transcriptional shift mediated by heat shock factors.^[6] Upon activation, the HSR induces a temporary halt in normal protein synthesis to redirect resources toward HSP production, thereby enhancing cell survival under stress.^[7] This inhibition occurs through phosphorylation of translation initiation factors like eIF2α, allowing selective translation of HSP mRNAs.^[8] Activation thresholds vary by organism; for instance, in mammals, the HSR is typically induced at temperatures above 41–42°C,^[9] while in yeast, it occurs around 37–39°C,^[10] reflecting adaptations to physiological norms.

Evolutionary aspects

The heat shock response (HSR) is a phylogenetically conserved mechanism observed across all domains of life, from prokaryotes to eukaryotes, underscoring its fundamental role in cellular adaptation to proteotoxic stress. In prokaryotes such as Escherichia coli, the HSR is regulated by the alternative sigma factor σ³² (encoded by the rpoH gene), which directs RNA polymerase to promoters of heat shock genes, enabling rapid induction upon temperature elevation.^[11] This prokaryotic system shares functional homology with eukaryotic counterparts, where heat shock factors (HSFs) bind to conserved heat shock elements (HSEs) in gene promoters to activate transcription. Homologous heat shock proteins (HSPs), particularly the Hsp70 family, exhibit remarkable sequence conservation across kingdoms, with core domains preserved from bacteria to mammals, facilitating protein refolding and preventing aggregation under stress.^[12] For instance, bacterial DnaK (Hsp70 ortholog) and eukaryotic Hsp70 share structural motifs essential for ATP-dependent chaperone activity, reflecting an ancient evolutionary origin predating the last universal common ancestor.^[6] The evolutionary origins of the HSR likely trace back to primordial cellular needs for maintaining proteostasis amid environmental fluctuations, such as temperature shifts in early Earth's variable conditions. Evidence from genomic analyses reveals ancient HSEs—consisting of inverted repeats of the pentameric motif nGAAn—as conserved cis-regulatory elements in promoter regions of HSP genes across diverse taxa, suggesting these binding sites emerged early in evolution to coordinate stress-inducible transcription.^[13] In eukaryotes, the HSR pathway, including HSF-HSE interactions, is among the most ancient transcriptional programs, with phylogenetic reconstructions indicating that major HSP families (Hsp70, Hsp90, Hsp40) diversified through gene duplications following the prokaryote-eukaryote divergence, optimizing chaperone networks for proteotoxic challenges.^[12] This conservation highlights the HSR's adaptive value in countering protein misfolding, a universal threat intensified by thermal variability in ancestral environments. Variations in HSR activation thresholds reflect ecological adaptations in different organismal groups. In poikilotherms, such as the rainbow trout (Oncorhynchus mykiss), HSF1 activation and maximal HSR occur at lower temperatures (e.g., 10–15°C below those in somatic cells of the same organism) compared to homeotherms like mammals, where thresholds are typically around 42–43°C, allowing poikilotherms to respond to broader environmental temperature swings without lethal overheating.^[14] In plants, the HSR integrates responses to multiple abiotic stressors beyond heat, including drought; for example, heat shock factor HSFA3 mediates signaling that enhances thermotolerance when pre-exposed to water deficit, enabling cross-protection via shared HSP induction.^[15] These differences in activation sensitivity—lower in ectothermic poikilotherms and plants versus endothermic homeotherms—illustrate evolutionary tuning to habitat-specific thermal regimes and compound stresses. The adaptive benefits of the HSR prominently include enhanced survival in fluctuating environments and contributions to longevity. In model organisms like Caenorhabditis elegans, mild heat shocks induce hormesis, where a single early-life exposure extends lifespan by approximately 20% through upregulation of HSPs like Hsp16 and Hsp70, while repeated mild shocks amplify this to 50% by bolstering proteostasis and stress resistance.^[16] This mechanism links the HSR to longevity pathways, such as those involving HSF-1 and insulin signaling, promoting resilience to intermittent stressors like temperature oscillations in natural habitats.^[17] Overall, the HSR's evolutionary persistence confers a selective advantage by mitigating protein damage, thereby supporting organismal fitness across diverse, unpredictable ecological niches.

Induction and Regulation

Stress detection and signaling pathways

The heat shock response (HSR) is initiated by molecular sensors that detect proteotoxic stress, such as protein misfolding or denaturation caused by elevated temperatures, leading to the activation of intracellular signaling cascades. In eukaryotic cells, the unfolded protein response (UPR) serves as a key sensor for endoplasmic reticulum (ER) stress, where accumulation of unfolded proteins triggers sensors like IRE1 and PERK. IRE1, an ER transmembrane protein, oligomerizes upon sensing misfolded proteins via its luminal domain, activating its kinase and endoribonuclease activities to splice XBP1 mRNA and initiate adaptive responses. Similarly, PERK phosphorylates eIF2α to attenuate global translation while selectively upregulating stress genes, including those involved in HSR. These UPR sensors are particularly activated during heat stress, as hyperthermia induces protein unfolding in the ER, linking ER homeostasis to the broader HSR.^[18]^[19] For direct heat sensing, mechanisms involve changes in plasma membrane fluidity and conformational shifts in heat shock factors (HSFs). Heat-induced alterations in membrane lipid composition increase fluidity, activating thermosensitive ion channels and signaling proteins that propagate the stress signal intracellularly. In parallel, monomeric HSF1, the primary regulator in mammals, trimerizes upon heat exposure, a process facilitated by the release from inhibitory chaperones like HSP90, allowing nuclear translocation and integration of stress signals. This trimerization is a direct thermosensory event, independent of upstream kinases in some contexts. In plants, additional heat sensors include cyclic nucleotide-gated channels (CNGCs) that mediate calcium influx in response to temperature shifts.^[20]^[21]^[22] Signaling pathways converge to amplify and specify the HSR. Oxidative stress, often co-occurring with heat, activates the MAPK/ERK pathway, where reactive oxygen species (ROS) phosphorylate ERK kinases, leading to enhanced HSF1 activity and cytoprotective gene expression. For heavy metal stressors like cadmium, calcium influx through plasma membrane channels triggers calmodulin-dependent signaling, which modulates HSF phosphorylation and HSR induction via oxidative intermediates. These pathways integrate at the HSF1 level, where multisite phosphorylation by kinases such as ERK and calcium-calmodulin kinases fine-tunes HSF1 trimer stability and transcriptional potency, ensuring a proportional response to stress intensity. In plants, MAPK cascades similarly relay oxidative signals to HSFs.^[23]^[24]^[25]^[26]^[27] Negative feedback mechanisms attenuate the HSR to prevent overactivation. Upon HSR induction, newly synthesized HSP70 binds to trimeric HSF1, promoting its monomerization and nuclear export, thus repressing further transcription in a classic negative feedback loop. This HSP70-HSF1 interaction ensures transient HSR, restoring homeostasis post-stress. In Arabidopsis, prion-like domains (PrDs) in sensory HSFs (e.g., HSFA1) confer HSR memory; heat-induced PrD conformational changes enable phase-separated condensates that persist, priming faster reactivation upon recurrent stress, as shown in recent structural studies.^[28]

Transcriptional control by heat shock factors

The heat shock response (HSR) is primarily orchestrated at the transcriptional level by heat shock factors (HSFs), which are transcription factors that bind to specific promoter elements to induce the expression of heat shock proteins (HSPs) and other protective genes in response to proteotoxic stress.^[29] In mammals, HSF1 serves as the principal regulator, activating a broad array of target genes upon heat shock or other stressors by transitioning from an inactive state to an active DNA-binding form.^[30] This process ensures rapid and coordinated upregulation of cytoprotective machinery, distinguishing HSF-mediated transcription from basal gene expression.^[31] HSF1 possesses a modular structure that enables its stress-responsive functions, featuring an N-terminal DNA-binding domain (DBD) with a helix-turn-helix motif for sequence-specific recognition, an adjacent oligomerization domain composed of hydrophobic repeats (HR-A and HR-B) that facilitate trimerization, and a C-terminal transactivation domain (TAD) responsible for recruiting transcriptional co-activators.^[32] Additionally, HSF1 contains multiple phosphorylation sites, particularly in the serine-proline rich region between the DBD and oligomerization domain, which are critical for modulating its activity; hyperphosphorylation at sites such as Ser230, Ser326, and Ser230/326 enhances DNA binding and transcriptional potency during stress.^[33] These structural elements allow HSF1 to integrate stress signals into precise gene activation.^[34] Upon exposure to heat or proteotoxic stress, HSF1 undergoes a conformational shift from monomeric to trimeric form, driven by the release of inhibitory interactions with HSPs such as HSP90, enabling nuclear translocation and subsequent binding to heat shock elements (HSEs) in target gene promoters.^[35] The trimerization process exposes the TAD, promoting recruitment of the transcriptional machinery and rapid induction of HSP genes.^[31] This activation is further amplified by upstream signaling pathways that converge on HSF1, such as those involving protein kinase cascades.^[9] The consensus HSE sequence consists of inverted pentameric repeats of the motif nGAAn (where n is any nucleotide), typically arranged as tandem arrays of at least three units (e.g., 5'-nGAAnnTTCnnGAAn-3') to form head-to-head or tail-to-tail orientations that support cooperative binding by HSF trimers.^[36] Cooperative binding enhances transcriptional efficiency, as multiple HSE modules allow stable trimer association and synergistic activation of promoters, with structural studies revealing a triangular arrangement of DBDs that clamps DNA for high-affinity interaction.^[32] HSF activity is tightly regulated by post-translational modifications to prevent excessive or prolonged responses. Phosphorylation not only activates HSF1 but also contributes to its attenuation through feedback mechanisms, while SUMOylation at lysine 298 promotes DNA binding initially but later facilitates disassembly of the transcriptional complex, aiding recovery from stress.^[37] Acetylation and ubiquitination further modulate stability and nuclear export.^[9] Isoform differences are evident between HSF1 and HSF2; HSF1 primarily drives acute stress responses, whereas HSF2, which forms heterotrimers with HSF1, is more constitutively active and crucial for developmental processes like erythropoiesis and spermatogenesis, with distinct target gene preferences due to variations in their TADs.^[38] In plants, HSFs are classified into three classes (A, B, and C) based on insertions in the HR-A/B region of the oligomerization domain, with class A (e.g., HSFA1, HSFA2) acting as transcriptional activators that induce HSP genes during abiotic stresses like heat and drought, while class B (e.g., HSFB1) functions as repressors to fine-tune the response post-stress.^[39] Class C members are less characterized but contribute to stress memory. Recent analyses highlight the expansion of these classes in crops like maize, where they coordinate thermotolerance through HSE binding and interactions with other regulators.^[40]

Core Components

Heat shock proteins classification

Heat shock proteins (HSPs) are grouped into families primarily based on their approximate molecular weights, reflecting their structural and functional diversity as molecular chaperones induced under cellular stress. The major families include the Hsp100 (approximately 100 kDa), Hsp90 (90 kDa), Hsp70 (70 kDa), Hsp60 (60 kDa), Hsp40 (40 kDa), and small HSPs (sHSPs, 12-43 kDa).^[41]^[42] The Hsp100 family consists of AAA+ ATPases that function as disaggregases, resolving protein aggregates by threading polypeptides through their central pore.^[43] The Hsp90 family comprises ATP-dependent chaperones that promote the folding and stability of client proteins, often in late-stage maturation.^[44] Hsp70 family members, also ATP-dependent, facilitate the folding of nascent polypeptides and the refolding of stress-damaged proteins by cycling between ATP- and ADP-bound states.^[45] The Hsp60 family includes GroEL-like chaperonins that form oligomeric cages to enclose and fold substrate proteins in an ATP-dependent manner, with bacterial GroEL serving as the prototypical example.^[46] Hsp40 proteins act as co-chaperones, typically stimulating the ATPase activity of Hsp70 partners to enhance substrate binding and transfer.^[47] In contrast, sHSPs operate as ATP-independent holdases, forming dynamic oligomers that sequester misfolded proteins to prevent aggregation until handover to other chaperones.^[48] Nomenclature for HSPs is standardized across species to highlight evolutionary conservation, with bacterial homologs like DnaK (an Hsp70 equivalent) and DnaJ (an Hsp40 equivalent) sharing core domains and mechanisms with eukaryotic counterparts.^[49] In humans, the HSP superfamily encompasses over 95 genes distributed among these families, encoding both cytosolic and organelle-specific variants.^[50] HSP expression is rapidly upregulated, often within minutes to hours of stress onset, through transcriptional activation where heat shock factors bind to heat shock elements (HSEs) in promoter regions.^[7] Many HSPs exist in constitutive forms, such as Hsc70 (a basal Hsp70 variant involved in routine protein handling), alongside stress-inducible isoforms like Hsp70, which are minimally expressed under normal conditions but surge dramatically in response to proteotoxic challenges.^[51] Broadly, HSP families divide into ATP-dependent classes (Hsp100, Hsp90, Hsp70, Hsp60), which harness nucleotide hydrolysis for active remodeling; Hsp40 act as non-ATPase co-chaperones; and ATP-independent classes (primarily sHSPs), which rely on oligomerization for passive protection.^[42]

Chaperone functions in protein handling

Heat shock proteins (HSPs) serve as molecular chaperones that maintain protein quality control by assisting in the folding of newly synthesized polypeptides, preventing the aggregation of misfolded intermediates, refolding denatured proteins, and targeting irreparable ones for degradation via pathways such as the ubiquitin-proteasome system.^[52] These functions are ATP-dependent in larger HSP families, ensuring efficient handling of stress-induced protein damage without altering the primary sequence of substrates.^[52] The Hsp70 family exemplifies these core chaperone activities through an allosteric cycle regulated by nucleotide binding and hydrolysis. In the ATP-bound state, Hsp70 adopts an open conformation with low affinity for substrates, facilitating rapid binding and release of polypeptides.^[53] ATP hydrolysis, stimulated over 1000-fold by co-chaperones like Hsp40 (also known as DnaJ in bacteria), transitions Hsp70 to the ADP-bound state, closing the substrate-binding domain and trapping unfolded or misfolded proteins with high affinity.^[53] This cycle prevents aggregation by shielding hydrophobic regions and promotes folding through iterative binding-unfolding events; for refolding, Hsp70 collaborates with nucleotide exchange factors (e.g., GrpE in bacteria) to release ADP and reset the cycle, while irreparable substrates are directed to degradation via ubiquitin ligases like CHIP.^[53] The binding affinity in this process is quantified by the dissociation constant K_d, which drops to approximately 6.5 nM in the Mg²⁺- and Pi-stabilized ADP-bound state, compared to micromolar levels in the ATP-bound state, enabling tight yet transient substrate interactions.^[54] Hsp90 performs specialized chaperone functions, particularly in the maturation of metastable client proteins such as steroid hormone receptors and protein kinases, often within multi-chaperone complexes.^[55] Unlike Hsp70, Hsp90's ATPase cycle involves N-terminal dimerization upon ATP binding, which closes a lid over the nucleotide site and activates the catalytic loop for hydrolysis, driving conformational changes that stabilize and activate clients.^[55] Co-chaperones like HOP bridge Hsp70 and Hsp90 to deliver substrates, such as glucocorticoid receptors, inhibiting Hsp90's ATPase to allow loading, while Cdc37 facilitates kinase maturation by similarly modulating activity; Aha1 then accelerates the cycle for release of mature proteins.^[55] This machinery ensures proper posttranslational maturation rather than de novo folding, preventing client aggregation during stress.^[55] Small heat shock proteins (sHSPs), such as Hsp27 and αB-crystallin, act primarily as ATP-independent holdases that bind partially denatured proteins to prevent irreversible aggregation under stress.^[56] Through dynamic oligomerization via their α-crystallin domains, sHSPs sequester exposed hydrophobic regions of substrates, maintaining them in a soluble, folding-competent state for subsequent handover to ATP-dependent chaperones like Hsp70 for refolding.^[56] In yeast and bacteria, the related Hsp104 (an Hsp100 family member) provides disaggregase activity, using ATP-powered hexameric rings to extract and solubilize proteins from aggregates, often in cooperation with Hsp70, thereby rescuing stressed proteomes.^[57]

Biological Functions

Cytoprotection and homeostasis

The heat shock response (HSR) plays a central role in maintaining cellular proteostasis by restoring the protein folding landscape through the induction of molecular chaperones, which refold misfolded proteins and prevent their aggregation. This process reduces endoplasmic reticulum (ER) stress by enhancing the activity of chaperones like BiP (an HSP70 family member), which binds to ER stress sensors such as IRE1, PERK, and ATF6 to inhibit the unfolded protein response until proteostasis is restored.^[58] HSR also integrates with autophagy for the clearance of irreparably damaged proteins; for instance, HSF1 upregulates autophagy-related genes like ATG7, while HSP70 modulates autophagic flux by inhibiting mTOR under certain stresses, ensuring coordinated degradation of protein aggregates.^[59] This interplay is evident in scenarios like heat or exercise stress, where early autophagy clears debris, followed by HSR-driven refolding to sustain long-term proteostasis.^[60] In terms of cytoprotection, HSR inhibits apoptosis by intervening in mitochondrial pathways; HSP70, for example, acts downstream of cytochrome c release to prevent caspase-3 activation and DNA fragmentation, as demonstrated in heat-stressed cells where HSP70 overexpression reduces apoptotic markers by 3.6–4.0-fold.^[61] HSPs further safeguard organelles like mitochondria during oxidative stress by activating manganese superoxide dismutase (Mn-SOD) to neutralize reactive oxygen species (ROS) and stabilizing mitochondrial membrane potential, thereby limiting damage from ischemia-reperfusion or ROS overload.^[62] These mechanisms, including chaperone-assisted macroautophagy, enhance cellular survival without directly refolding individual proteins, as explored in core chaperone functions.^[63] HSR links to broader homeostasis by influencing circadian rhythms and metabolic adaptation; circadian clock components, such as ELF3, act as thermosensors that gate heat-responsive gene expression, optimizing energy allocation and protein synthesis in a time-of-day-dependent manner to support metabolic balance.^[64] Knockout models underscore this role: HSF1-deficient mice exhibit disrupted redox homeostasis, with a 40% lower GSH/GSSG ratio, elevated mitochondrial superoxide (43% higher), and increased permeability transition pore opening, rendering them hypersensitive to oxidative and inflammatory stresses.^[65] These mice also show developmental defects, such as chorioallantoic placenta abnormalities leading to prenatal lethality in 85–99% of cases, highlighting HSF1's necessity for stress resilience.^[66] Specific evidence includes HSR activation extending lifespan in Drosophila by 4–30% through enhanced proteostasis and stress resistance, as seen with Hsp70 or small HSP overexpression.^[67] Moreover, 2024 studies on Drosophila embryos reveal heat tolerance mechanisms beyond classical HSR, involving oxidative stress response tuning via stress-activated kinases like JNK and miRNA-mediated robustness to maintain developmental patterning under elevated temperatures.^[68]

Roles in stress adaptation and memory

The heat shock response (HSR) facilitates long-term cellular adaptation through a priming effect, where exposure to mild stress, such as 40°C for a short duration, enhances tolerance to subsequent severe heat stress by maintaining elevated levels of heat shock proteins (HSPs). This acquired thermotolerance allows cells to survive temperatures that would otherwise be lethal, as demonstrated in plant models where priming reprograms metabolic pathways to sustain HSP expression and protect protein homeostasis during recurrent heat episodes. In rice seedlings, for instance, thermopriming induces persistent changes in carbohydrate metabolism and antioxidant defenses, conferring resistance to lethal heat up to 45°C for several days post-priming. Similarly, in Arabidopsis, intermittent mild heat stress activates sustained HSP70 and HSP101 accumulation, enabling recovery from acute shocks that impair non-primed cells. Stress memory in the HSR is mediated by epigenetic modifications, particularly hypermethylation of histone H3 at lysine 4 (H3K4me3) on heat shock elements (HSEs) in promoter regions of HSP genes, which poises loci for rapid reactivation upon re-exposure to stress. This hit-and-run mechanism involves transient binding of heat shock factor A2 (HSFA2), which recruits histone methyltransferases to establish long-lasting chromatin marks, ensuring transcriptional memory for up to 5-7 days in plants. Recent studies in Arabidopsis have further revealed that prion-like domains (PrDs) in upstream sensory heat shock factors (HSFs), such as HSFA1d, undergo heat-induced phase separation and aggregation, facilitating the transmission of activation signals across cell generations and perpetuating memory in meristematic tissues. These PrD-mediated aggregates act as heritable thermosensors, amplifying HSR in progeny under recurring stress conditions. The HSR also provides cross-stress protection, where heat-induced HSPs confer resistance to unrelated stressors like hypoxia or chemical oxidants. In mammalian cells, heat acclimation stabilizes hypoxia-inducible factor 1α (HIF-1α) via HSP90, enhancing survival during oxygen deprivation by mitigating oxidative damage upon reoxygenation. This cross-tolerance extends to chemical insults, as HSP70 upregulation from heat priming reduces toxicity from reactive oxygen species-generating agents in yeast and plant models. In developmental contexts, such as zebrafish embryogenesis, the HSR supports adaptation by regulating HSP expression during gastrulation and somitogenesis, where mild heat pulses induce tolerance to subsequent thermal fluctuations, ensuring proper neural and muscular patterning without disrupting morphogenesis.

Clinical and Pathological Relevance

Involvement in diseases and inflammation

The heat shock response (HSR) plays a pivotal role in resolving acute inflammation by mitigating proteotoxic stress and suppressing pro-inflammatory signaling pathways. For instance, Hsp70 inhibits NF-κB activation, thereby dampening inflammatory responses in conditions such as pulmonary tuberculosis and brain ischemia.^[69]^[70] This anti-inflammatory action of Hsp70 extends to extracellular contexts, where it promotes a shift toward resolution by interacting with immune cells like macrophages.^[71] Similarly, the broader HSR orchestrates the clearance of damaged proteins and lipids during inflammation resolution, preventing escalation to chronic states.^[72] In chronic inflammation, failure of the HSR contributes to persistent immune dysregulation and links to autoimmune diseases. A 2024 review highlights that impaired HSR allows unresolved proteotoxic stress to sustain low-grade inflammation, fostering autoimmunity in rheumatic disorders through dysregulated heat shock protein expression.^[73]^[74] Elevated levels of heat shock proteins, such as Hsp70, are observed in inflamed tissues and serum, reflecting systemic inflammation and oxidative stress while attempting to counteract T cell-mediated reactions.^[75] Experimental models demonstrate that HSF1 knockout exacerbates inflammation, with increased TNFα levels, heightened susceptibility to endotoxins, and reduced survival under stress, underscoring HSF1's role in restraining inflammatory cascades.^[72] Dysregulated HSR contributes to various diseases, particularly those involving protein aggregation and stress overload. In neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Hsp70 fails to effectively manage misfolded proteins like SOD1 mutants, leading to glial inflammation and motor neuron loss; enhanced Hsp70 expression shows neuroprotective potential in models.^[76]^[77] In cardiovascular diseases, Hsp90 promotes atherosclerosis by stabilizing pro-atherogenic factors and acting as an autoantigen in plaques, with overexpression linked to plaque instability and immune responses in affected arteries.^[78]^[79] The HSR also adapts to hypoxia-related conditions, including tumors, where hypoxia induces Hsp70 oligomerization and upregulation to maintain proteostasis amid oxygen deprivation and metabolic shifts.^[80]^[81] Pathological shifts in the HSR during aging lead to overload and proteostasis collapse, exacerbating disease susceptibility. Chronic stress accumulates misfolded proteins, overwhelming chaperone capacity and impairing the HSR, which results in widespread proteotoxic damage and inflammation in aged tissues.^[82]^[83] This collapse is evident in models where diminished HSR correlates with proteostasis network deregulation, linking aging to heightened vulnerability in neurodegenerative and inflammatory pathologies.^[84]

Therapeutic targeting and applications

The heat shock response (HSR) has emerged as a promising target for therapeutic intervention, particularly through pharmacological modulation of key components like heat shock proteins (HSPs) and heat shock factor 1 (HSF1). Inhibitors of HSP90, such as derivatives of geldanamycin (e.g., tanespimycin and 17-AAG), disrupt the stability of client proteins including oncogenic drivers like HER2 and BRAF, leading to their proteasomal degradation and inhibition of tumor growth.^[85] These agents sensitize cancer cells to chemotherapy by impairing adaptive stress responses, enhancing the efficacy of drugs like paclitaxel in preclinical models.^[86] Recent 2025 reviews highlight emerging resistance mechanisms, such as compensatory upregulation of other chaperones, underscoring the need for combination strategies to overcome these limitations.^[87] In clinical settings, HSP90 inhibitors have shown activity in breast cancer trials. For instance, a phase II trial of tanespimycin in HER2-positive metastatic breast cancer reported an overall response rate of 22% and clinical benefit in 59% of patients pretreated with trastuzumab.^[88] Similarly, ganetespib combined with standard neoadjuvant chemotherapy in high-risk early-stage breast cancer demonstrated improved pathological complete response rates in exploratory analyses, though larger confirmatory studies are ongoing.^[89] As of 2024, over 20 HSP90 inhibitors have advanced to clinical trials across various cancers, with 186 trials registered, though challenges include dose-limiting toxicities like ocular and hepatic effects.^[90] On the activation side, pharmacological inducers of HSF1 offer potential for cytoprotective applications in neurodegenerative diseases. Celastrol, a triterpenoid derived from Tripterygium wilfordii, activates HSF1 by promoting its trimerization and nuclear translocation, leading to upregulation of HSPs that mitigate protein aggregation and neuronal toxicity in models of Parkinson's and Alzheimer's diseases.^[91] Preclinical studies demonstrate celastrol's neuroprotective effects through enhanced proteostasis and reduced oxidative stress in dopaminergic neurons.^[92] Arimoclomol, an HSF1 co-inducer that amplifies stress-induced HSP expression, has been evaluated in amyotrophic lateral sclerosis (ALS). A 2025 meta-analysis of randomized controlled trials reported a non-significant modest slowing of ALS Functional Rating Scale-Revised (ALSFRS-R) decline by 2.64 points compared to placebo (P=0.15).^[93] Safety profiles indicate tolerability, but over-activation risks include off-target proteotoxic stress and inflammation.^[94] Beyond direct pharmacology, HSR modulation enhances hyperthermia-based cancer therapies. Modulated electro-hyperthermia (mEHT) induces localized tumor heating (40-43°C), triggering HSR and HSP expression; combining it with HSF1 inhibitors like KRIBB11 suppresses protective HSP70/90, potentiating apoptosis and radiosensitization in preclinical glioma and breast cancer models.^[95] In ischemia-reperfusion injury, HSR activation confers organ protection; for example, HSP70 overexpression reduces infarct size in myocardial models by inhibiting apoptosis and inflammation, while pharmacological preconditioning with geranylgeranylacetone upregulates HSPs to mitigate renal damage post-ischemia.^[96]^[97] Therapeutic challenges persist, including balancing efficacy with toxicity from excessive HSR suppression (e.g., systemic proteotoxicity) or hyperactivation (e.g., pro-tumorigenic effects in chronic settings), necessitating biomarker-guided approaches.^[87]^[98]

History

Early discoveries

The heat shock response was first observed in 1962 by Ferruccio Ritossa, who noted a novel pattern of chromosomal puffing in the salivary glands of Drosophila busckii larvae exposed to elevated temperatures of 37–40°C, suggesting the activation of new gene transcription in response to thermal stress.^[3] These "heat shock puffs" were recognized as sites of intense RNA synthesis, distinct from developmental puffing patterns, and were initially interpreted as a specific transcriptional response to temperature elevation, with similar effects induced by chemical agents like 2,4-dinitrophenol (DNP).^[3] Building on these cytological observations, early biochemical studies in the 1970s focused on protein synthesis changes during heat shock. In 1974, Alfred Tissières and colleagues used radiolabeling with radioactive amino acids to demonstrate that heat-shocked salivary glands of Drosophila melanogaster larvae produced a set of novel polypeptides, now known as heat shock proteins (HSPs), while suppressing most normal protein synthesis; these HSPs ranged in molecular weight from 20 to 100 kDa, with prominent bands at 70 kDa and 83 kDa.^[99] This work established HSPs as key molecular components of the heat shock response, linking the chromosomal puffs to the synthesis of stress-inducible proteins. Advancing into the 1980s, molecular cloning efforts revealed the genomic organization underlying HSP production. In 1978, John T. Lis, Louise Prestidge, and David S. Hogness cloned the genes encoding the major 70 kDa HSP (Hsp70) from Drosophila melanogaster, identifying tandemly repeated copies at chromosomal loci 87A and 87C that were transcriptionally activated upon heat shock.^[100] By the mid-1980s, the Hsp70 gene had been fully sequenced, confirming its inducibility and conservation across species.^[101] In the late 1980s, HSPs were increasingly recognized for their functional roles beyond mere induction, particularly as molecular chaperones that assist in protein folding and prevent aggregation under stress. Hugh Pelham proposed in 1986 that Hsp70 and related proteins facilitate the refolding of denatured polypeptides during recovery from heat shock, drawing parallels to bacterial stress proteins like DnaK.^[102] This concept was formalized by R. John Ellis in 1987, who coined the term "molecular chaperone" to describe proteins like HSPs that mediate the correct assembly of other polypeptides without being part of their final structure.^[103]

Key research milestones

In the 1990s, significant advances elucidated the molecular mechanisms underlying the heat shock response (HSR), particularly through the identification and characterization of heat shock factor 1 (HSF1) as the primary transcription factor orchestrating HSP gene expression. HSF1 was cloned and shown to bind heat shock elements (HSEs) in promoter regions, enabling trimerization and activation upon stress, as detailed in foundational studies on its DNA-binding properties.^[104] This work, building on earlier observations, shifted research from phenotypic descriptions of stress-induced protein synthesis to precise regulatory pathways.^[105] During the 2000s, investigations into chaperone complexes revealed the intricate role of Hsp90 in stabilizing client proteins involved in signaling and proteostasis. William B. Pratt and colleagues demonstrated that Hsp90 functions within a dynamic multiprotein machinery, including Hsp70, Hop, Hsp40, and p23, to regulate the maturation and trafficking of signaling proteins like steroid receptors, highlighting its essential role beyond mere refolding.^[106] These findings integrated HSR into broader cellular networks, emphasizing chaperone cycles in maintaining protein homeostasis under stress.^[107] The 2010s marked a pivotal expansion of HSR research into disease contexts, particularly cancer, where HSF1 emerged as a driver of malignancy independent of classical heat shock programs. In 2011, studies showed elevated nuclear HSF1 levels correlate with poor prognosis in breast cancer, promoting tumor progression by supporting proteomic stability and repressing antitumor immunity.^[108] This era also linked HSF1 to oncogenic signaling, revealing its co-option for cancer cell survival, as evidenced by transcriptional programs that enhance proliferation and metastasis.00826-4) Recent developments from 2023 to 2025 have further connected HSR to inflammation resolution and adaptive memory. Research demonstrated that HSR activation facilitates the transition from pro-inflammatory to pro-resolving states, countering chronic inflammation in degenerative diseases through HSF1-mediated HSP induction, though its suppression contributes to pathology.^[72] In plants, prion-like domains in sensory HSFs were identified as mediators of HSR activation and long-term memory, enabling heritable stress priming via conformational changes.^[109] Additionally, studies on embryonic development revealed nuanced HSR dynamics in Drosophila, where heat stress beyond canonical pathways influences biochemical responses and developmental robustness.^[110] Key contributors to these milestones include Susan Lindquist, whose work on chaperone functions illuminated HSR's role in proteostasis and disease, and Richard Morimoto, who advanced understanding of HSF1 regulation and its integration into stress signaling networks.00782-3) Overall, these breakthroughs have transformed HSR from a descriptive stress response into a mechanistic framework intertwined with proteostasis, influencing therapeutic strategies across biology.^[111]

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Activation of the heat shock transcription factor by hypoxia in ...
These findings provide strong evidence that hypoxia and heat shock induce expression of the HSP70 gene by similar, if not identical, mechanisms. Full text. PDF.
[6]
Stress (Heat Shock) Proteins | Circulation Research
Characteristically, general protein synthesis is inhibited after extreme heat challenge as a result of phosphorylation of initiation factors such as eIF2α, ...
[7]
Chaperone Hsp27 inhibits translation during heat shock by binding ...
Heat shock activates a specific transcriptional response and largely inhibits protein synthesis, establishing conditions that favor the exclusive translation ...Missing: temporary halt
[8]
Regulation of the mammalian heat shock factor 1 - FEBS Press - Wiley
Jan 4, 2017 · In humans, temperatures above 41–42 °C induce the heat shock response ... response, HSF1 activation and heat shock protein synthesis. PLoS One ...<|control11|><|separator|>
[9]
Regulon and promoter analysis of the E. coli heat-shock factor, σ 32 ...
The heat-shock response (HSR), a universal cellular response to heat, is crucial for cellular adaptation. In Escherichia coli, the HSR is mediated by the ...
[10]
The evolution of heat shock protein sequences, cis-regulatory ... - NIH
Jan 19, 2016 · We reconstructed the evolutionary history of three families of Heat Shock Proteins (Hsp90, Hsp70, Hsp40), the primary molecular chaperones ...
[11]
https://genesdev.cshlp.org/content/20/13/1776.long
[12]
Varying Architecture of Heat Shock Elements Contributes to Distinct ...
The heat shock transcription factor (HSF) binds to cis-regulatory motifs known as heat shock elements (HSEs) to mediate the transcriptional response of HSF ...
[13]
HSF1 Activation Occurs at Different Temperatures in Somatic and ...
In the present study, we show that in the poikilotherm rainbow trout, the maximal heat shock response of male germ cells, that are located in the same body ...
[14]
Evolutionary Origin, Gradual Accumulation and Functional ...
Feb 1, 2018 · Plants, as sessile organisms, evolved a complex and functionally diverse heat shock factor (HSF) gene family to cope with various ...Missing: HSEs | Show results with:HSEs
[15]
Longevity and stress in Caenorhabditis elegans - PubMed Central
While a single heat shock early in life gives rise to a 20% longer lifespan, multiple mild heat shocks throughout the C. elegans lifetime increase its lifespan ...
[16]
Temperature-Dependent Regulation of Proteostasis and Longevity
Mar 23, 2022 · This review summarizes how proteostasis and longevity are modulated by changes in environmental temperature, focusing on studies in Caenorhabditis elegans.
[17]
Structure and Molecular Mechanism of ER Stress Signaling by the ...
The UPR instigates a transcriptional and translational response to ER stress. The three UPR activator proteins, IRE1, PERK, and ATF6 give rise to three separate ...
[18]
The Unfolded Protein Response: Integrating Stress Signals Through ...
Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to ...<|control11|><|separator|>
[19]
The Role of the Membrane-Initiated Heat Shock Response in Cancer
Apr 27, 2016 · The “membrane thermosensor” theory suggests that heat shock can induce changes in the fluidity of membranes, leading to remodeling of the ...
[20]
Molecular mechanism of thermosensory function of human heat ...
Jan 19, 2016 · In the activated state Hsf1 forms trimers or higher order oligomers and binds to its response elements in heat shock gene promoters (Clos et al.<|control11|><|separator|>
[21]
The heat shock response in plants: new insights into modes of ...
Oct 16, 2024 · This review summarizes recent discoveries in heat shock sensing and responses in plants. Such discoveries have revealed that different ...The Heat Shock Response In... · Heat Stress Responses In The... · Nuclear Condensate Formation...<|control11|><|separator|>
[22]
壽Activation of the mitogen-activated protein kinase pathways by ...
Heat shock activates within minutes the major signaling transduction pathways involving mitogen-activated protein kinases, extracellular signal–regulated ...
[23]
The Mechanism of Heat Shock Activation of ERK Mitogen-activated ...
In the present study, we have demonstrated that ERK and JNK MAPKs, but not p38 MAPKs, are activated by 42 °C heat shock at 60 and 120 min.
[24]
Calcium and Cell Response to Heavy Metals: Can Yeast Provide an ...
This chapter focuses on the attempts done so far to elucidate the calcium-mediated response to heavy metal stress using the model organism Saccharomyces ...<|control11|><|separator|>
[25]
Calcium Signaling and the Response to Heat Shock in Crop Plants
In this review, we discuss the crucial role of Ca 2+ signaling in raising plant thermotolerance, and we explore its multifaceted contributions to various ...Missing: heavy | Show results with:heavy
[26]
Dynamic control of Hsf1 during heat shock
Nov 10, 2016 · Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate ...
[27]
Hsf1 and Hsp70 constitute a two-component feedback loop ... - eLife
Feb 2, 2018 · Dynamic regulation of the heat shock response depends on a negative feedback loop in which Hsf1 activates expression of Hsp70 and Hsp70 ...
[28]
Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70 ...
Jun 3, 2020 · Heat shock transcription factor 1 (Hsf1) is a central regulator of the heat shock response (HSR) in eukaryotic cells. This study demonstrates ...
[29]
Transcriptional response to stress is pre-wired by promoter ... - Nature
Aug 15, 2017 · Heat shock factor 1 (HSF1) is the prime regulator of heat stress-induced transcription, and a key player for maintaining protein homeostasis in ...
[30]
HSF1 at a glance | Journal of Cell Science
Jan 15, 2014 · HSF1 is characterized by an N-terminal helix-turn-helix DNA-binding domain and an adjacent oligomerization domain that consists of hydrophobic ...
[31]
HSF1 phosphorylation establishes an active chromatin state via the ...
Jul 29, 2022 · In response to heat shock, HSF1 is converted to a DNA-binding trimer by the release of chaperones, and its transcriptional activity is enhanced ...
[32]
Structures of heat shock factor trimers bound to DNA - PMC - NIH
Sep 24, 2021 · We present co-crystal structures of human HSF1 and HSF2 trimers bound to DNA, which reveal a triangular arrangement of the three DNA-binding domains (DBDs)
[33]
Repression of human heat shock factor 1 by phosphorylation
The ability of HSF1 to bind DNA is regulated by a structural transition from an inactive monomer to an active trimer (Sorger and Nelson 1989;. Westwood and Wu ...
[34]
Repression of Heat Shock Transcription Factor HSF1 Activation by ...
In a novel in vitro system, in which human HSF1 can be activated by nonnative protein, heat, and geldanamycin, addition of Hsp90 inhibits activation.
[35]
Pro-death signaling of cytoprotective heat shock factor 1 - Nature
Jan 29, 2020 · The HSE consensus sequence is a tandem array of at least three oppositely oriented “nGAAn” motifs or a degenerate version thereof. In most ...
[36]
Regulation of Heat Shock Transcription Factor 1 by Stress-induced ...
HSF1 is regulated by stress-induced SUMO-1 modification at lysine 298, which enables DNA binding and is a key modulator of HSF1 function.
[37]
Interplay between mammalian heat shock factors 1 and 2 in ...
Sep 3, 2021 · This review focuses mainly on HSF1 and HSF2 that are rare transcription factors forming either homo- or heterotrimers in mammals (Table 1).
[38]
Heat stress transcription factors as the central molecular rheostat to ...
Jul 26, 2024 · Heat stress transcription factors (HSFs) are the core regulators of the heat stress (HS) response in plants. HSFs are considered as a molecular rheostat.
[39]
Conserved & variable heat stress responses in maize/Setaria viridis
Apr 27, 2023 · The Heat Shock Factor (HSF) transcription factor family is a central and required component of plant heat stress responses and acquired ...<|control11|><|separator|>
[40]
List of 95 HSP family members classified into 6 sub ... - ResearchGate
List of 95 HSP family members classified into 6 sub-families according to their molecular weight (HSP110, HSP90, HSP70, HSP60, HSP40 and HSP20).
[41]
Size dependent classification of heat shock proteins: a mini-review
Molecular weight of sHSP varied from 15 to 43 kDa are also called heat shock protein β (HSPBs) and have a chaperoning function in the process of embryonic ...
[42]
Processive extrusion of polypeptide loops by a Hsp100 disaggregase
Jan 29, 2020 · Hsp100 disaggregases such as ClpB and Hsp104 are proposed to catalyse this reaction by translocating polypeptide loops through their central pore.Missing: disaggregases | Show results with:disaggregases
[43]
Hsp90: a specialized but essential protein-folding tool - PMC
At a molecular level, Hsp90 binds to substrate proteins, which are in a near native state and thus at a late stage of folding (Jakob et al., 1995) poised for ...
[44]
Bacterial Hsp70 resolves misfolded states and accelerates ... - Nature
Jan 17, 2020 · The KJE system mediates the folding of newly synthesized proteins and the refolding of proteins that unfolded under stress conditions such as ...
[45]
Molecular Chaperonin HSP60: Current Understanding and Future ...
HSP60, a 60 kDa molecular chaperonin primarily described as a GroEL/GroES system in Escherichia coli In humans, HSP60 chaperonin(s), also known as Cpn60 ...
[46]
Specification of Hsp70 Function by Hsp40 Co-chaperones - PubMed
Hsp40 (DnaJ-like proteins) family members are Hsp70 co-chaperones that determine the fate of Hsp70 clients by facilitating protein folding, assembly, and ...
[47]
Functional Diversity of Mammalian Small Heat Shock Proteins
The small heat shock proteins (sHSPs), whose molecular weight ranges from 12∼43 kDa, are members of the heat shock protein (HSP) family that are widely found in ...
[48]
Hsp70 - Wikipedia
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins.
[49]
Mutational landscape of HSP family on human breast cancer - Nature
May 30, 2024 · The Heat Shock Protein family (HSP) is composed of 95 genes subdivided into five subfamilies, these genes play critical roles in proteostasis in ...
[50]
Constitutive and Inducible Heat Shock Protein 70 Immunoreactivity ...
Moreover, Hsc70 is synthesized constitutively in mammalian cells and is only moderately stress-inducible, whereas Hsp70 is usually undetectable, under normal ...Missing: via HSEs
[51]
Chaperone function and mechanism of small heat-shock proteins
Small heat-shock proteins (sHSPs) are ubiquitous ATP-independent molecular chaperones that play crucial roles in protein quality control in cells.
[52]
Heat shock proteins: Biological functions, pathological roles, and ...
Aug 2, 2022 · Heat shock proteins (HSPs) are in charge of proteostasis and buffer the stresses. Malfunction of HSPs lead to many diseases. In this review, we ...
[53]
Hsp70 chaperones: Cellular functions and molecular mechanism
The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus ...Missing: seminal | Show results with:seminal
[54]
Biochemical and structural studies on the high affinity of Hsp70 ... - NIH
Upon ATP hydrolysis, the Hsp70 conformation changes from the ATP-bound state to the ADP-bound state, in which the substrate-binding pocket is covered by the α- ...
[55]
Mechanisms of Hsp90 regulation | Biochemical Journal
Hsp90 is responsible for the maturation of key signalling proteins including regulatory kinases [10–12], steroid hormone receptors [13] and transcription ...
[56]
The small heat shock proteins and their role in human disease - 2005
May 13, 2005 · Small heat shock proteins (sHSPs) function as molecular chaperones, preventing stress induced aggregation of partially denatured proteins ...<|separator|>
[57]
Structural basis for the disaggregase activity and regulation of Hsp104
Nov 30, 2016 · The Hsp104 disaggregase is a two-ring ATPase machine that rescues various forms of non-native proteins including the highly resistant amyloid fibers.
[58]
Endoplasmic reticulum stress: molecular mechanism and ... - Nature
Sep 15, 2023 · ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER.
[59]
Heat shock response and autophagy—cooperation and control - PMC
In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time ...
[60]
https://doi.org/10.1074/jbc.M113.462408
[61]
Heat Shock Protein 70 Inhibits Apoptosis Downstream of ...
We conclude that HSP70 acts as a strong suppressor of apoptosis acting downstream of cytochrome c release and upstream of caspase-3 activation.
[62]
Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion ...
Jan 31, 2021 · Heat shock proteins (HSPs) are molecular chaperones produced in response to oxidative stress (OS). These proteins are involved in the folding of ...
[63]
https://doi.org/10.1074/jbc.C400357200
[64]
The intersection between circadian and heat-responsive regulatory ...
The circadian clock plays a significant role in heat-responsive gene expression. In response to heat shock, cca1/lhy double mutants and prr7/9 double mutants ...
[65]
Mouse heat shock transcription factor 1 deficiency alters cardiac ...
Here we report that, in mice, HSF1 deficiency reduces cardiac expression of Hsp25, αB-crystallin and Hsp70, but not Hsp60 and Hsp90.
[66]
HSF1 is required for extra‐embryonic development, postnatal ...
In previous in vitro analysis of HSF1 functions, we have demonstrated that Hsf1−/− cells derived from mouse embryos exhibited markedly increased susceptibility ...Homozygous Hsf1 Mice... · Disruption Of Hsf1... · Disruption Of Hsf1 Increases...
[67]
Heat shock proteins and Drosophila aging - PMC - PubMed Central
Since their discovery in Drosophila, the heat shock proteins (Hsps) have been shown to regulate both stress resistance and life span.
[68]
Beyond the heat shock pathway: Heat stress responses in ...
As described in the introduction, HSF communicates shifts in temperature through trimerization and induction of the heat shock proteins. Some of these heat ...
[69]
Heat shock protein70 is implicated in modulating NF-κB activation in ...
Apr 27, 2017 · The inhibition of NF-κB activity indicates HSP70 plays a role in modulating the inflammatory responses during the process of pulmonary TB ...
[70]
Heat Shock Protein 70 as a Double Agent Acting Inside and Outside ...
Jul 26, 2020 · Hsp70 exhibits an immunosuppressive activity via, e.g., downregulation of the nuclear factor-kappa B (NF-κB) activation, and pharmacological ...
[71]
Systemic release of heat-shock protein 27 and 70 following severe ...
Jul 3, 2019 · Recent studies show that the presence of extracellular HSP 27 induces a shift towards anti-inflammatory pathways in macrophages via NF-κB ( ...<|separator|>
[72]
Heat shock response during the resolution of inflammation and its ...
The heat shock response (HSR) is a crucial biochemical pathway that orchestrates the resolution of inflammation, primarily under proteotoxic stress conditions.Review · Hsr At The Organismal Level... · Impaired Resolution Of...
[73]
Resolution of inflammation in chronic disease via restoration of the ...
Effective resolution of inflammation via the heat shock response (HSR) is pivotal in averting the transition to chronic inflammatory states.Review · Physiological Approaches · The Integrity Of The Hsr Can...
[74]
Heat shock (stress) proteins and autoimmunity in rheumatic diseases
Recent evidence indicates that heat shock or stress proteins (HSPs) may have an important role in the eitology / pathogenesis of RDs.
[75]
The detection and role of heat shock protein 70 in various ...
Increased serum levels of HSP70 reflect systemic inflammation and oxidative stress, and increases in HSP70 might dampen T cell-mediated inflammatory reactions ...Missing: inflamed | Show results with:inflamed
[76]
The role of heat shock proteins in Amyotrophic Lateral Sclerosis
In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the ...
[77]
Regional differences in the inflammatory and heat shock response ...
The results of this study suggest that impaired heat shock response in SOD1 G93A glia may contribute to the exacerbated inflammatory reactions observed in ALS ...Original Paper · Results · Experimental Procedures
[78]
The Role of HSP90 Inhibitors in the Treatment of Cardiovascular ...
Oct 31, 2022 · HSP90 plays a significant role in most cardiovascular diseases, including hypertension, pulmonary venous hypertension, atherosclerosis, and heart failure.
[79]
A novel autoantigen in human carotid atherosclerosis - ScienceDirect
These new findings, showing that HSP90 is overexpressed in plaque and serum from patients with atherosclerosis and induces an immune response in these patients, ...
[80]
Dynamics of heat shock protein 70 kDa in heat-shocked and hypoxic ...
We demonstrated that the HS response and hypoxia regulate HSPs through a new layer of complexity, oligomerization, in addition to classical cochaperone/NEF ...
[81]
Tumorigenesis: cell defense against hypoxia? - PubMed
Apr 22, 2013 · Cells respond to hypoxia by de-differentiation and an increase in heat shock proteins. Angiogenesis and deviation of inflammatory response ...
[82]
Navigating the landscape of protein folding and proteostasis - Nature
Oct 23, 2025 · This review also examines cellular stress response pathways, including the heat shock response (HSR) and the unfolded protein response (UPR) ...
[83]
A Futile Battle? Protein Quality Control and the Stress of Aging
Jan 22, 2018 · Without a functional HSR, heat stress can cause irreparable damage to the cell due to an accumulation of damaged and misfolded proteins, which ...
[84]
Proteostasis network deregulation signatures as biomarkers for ...
Dysregulation in these processes can lead to PN imbalances and proteostasis collapse in aging and diverse diseases, from age-onset neurodegenerative diseases to ...
[85]
Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy
Oct 20, 2024 · This review discusses the mechanism of action of geldanamycin, its pharmacokinetic properties, and the various approaches employed to alleviate ...
[86]
Combination therapy involving HSP90 inhibitors for combating cancer
Apr 17, 2024 · This review provides an overview of the use of combination therapy with HSP90 inhibitors and other anti-cancer therapies in clinical and preclinical studies
[87]
Combination Strategies with HSP90 Inhibitors in Cancer Therapy
Jul 22, 2025 · In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges ...
[88]
HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of ...
The current data reveal an overall response rate of 22% and clinical benefit rate of 59% for patients with HER2+ MBC pretreated and progressing on prior ...
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Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant ...
Dec 1, 2022 · We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer.
[90]
An update on the status of HSP90 inhibitors in cancer clinical trials
Jun 13, 2024 · To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov.
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Heat shock transcription factor 1 as a therapeutic target in ...
Celastrol-dependent proteasome inhibition could result in the accumulation of misfolded proteins, which could lead to the induction of HSF1 activity. Celastrol ...
[92]
Neuroprotective Effects of Celastrol in Neurodegenerative Diseases ...
This review focuses on the therapeutic efficacy and major regulatory mechanisms of celastrol to rescue damaged neurons, restore normal cognitive and sensory ...
[93]
Efficacy of Arimoclomol for Amyotrophic Lateral Sclerosis
Apr 7, 2025 · The results show that arimoclomol was associated with a slightly slower decline in ALSFRS-R scores compared to placebo, with a mean difference of 2.64.
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Safety and efficacy of arimoclomol in patients with early amyotrophic ...
We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. Methods: ORARIALS-01 was a multinational, randomised ...
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Heat shock factor 1 inhibition enhances the effects of modulated ...
Apr 8, 2024 · The mEHT-induced energy absorbed by tumor tissues results in temperature elevation, hence inducing the heat shock response (HSR)17.
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https://www.ahajournals.org/doi/abs/10.1161/01.CIR.0000101923.54751.77
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Role of heat shock protein 70 in hepatic ischemia-reperfusion injury ...
The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia-reperfusion injury and that extracellular HSP70 is not a significant ...
[98]
Opportunities and Challenges for Molecular Chaperone Modulation ...
Mounting evidence supports the concept that modulating chaperones can reduce protein misfolding and toxicity in neurons [1]. In most cases, however, the ...
[99]
https://doi.org/10.1016/0022-2836(74)90427-3
[100]
HEAT SHOCK TRANSCRIPTION FACTORS: Structure and Regulation
The heat shock response was discovered by Ritossa (1962), who observed an induction of specific chromosome puffs on the polytene chromosomes of Drosophila ...
[101]
Regulation of the heat shock transcriptional response
The stress signal that activates the heat shock response is widely held to be the flux of non-native, such as, nipfridid proteins (Morimoto et al. 1994b).
[102]
Regulation of signaling protein function and trafficking by the hsp90 ...
We have now developed a minimal system of five purified proteins-hsp90, hsp70, Hop, hsp40, and p23- that assembles stable receptor*hsp90 heterocomplexes.Missing: 2000s | Show results with:2000s
[103]
Pratt WB, Toft DORegulation of signaling protein function and ...
Aug 6, 2025 · This chaperone machinery is ATP-dependent, in which HSP90 binds to ATP and p23 stabilizes the complex. Both HSP70 and HSP40 also interact after ...
[104]
[PDF] High levels of nuclear heat-shock factor 1 (HSF1) are associated ...
Nov 8, 2011 · We have demonstrated that the multifaceted ability of HSF1 to promote survival in the face of lethal stressors is co-opted by cancer cells (6).
[105]
Heat stress responses in Drosophila development - PubMed - NIH
This review explores embryonic heat responses beyond the heat shock pathway. We examine the effects of heat from a biochemical standpoint.
[106]
Mechanisms tailoring the expression of heat shock proteins to ...
In this review, we will address the molecular mechanisms in different organisms and cell types that coordinate the expression of HSPs with signaling networks.