Search Results (578)

Type 2 diabetes (T2D) is a chronic metabolic disorder leading to increased cardiovascular risk and vascular dysfunction. Hyperglycemia, a hallmark of T2D, drives hypercontractility, thereby compromising vascular function. Heat shock protein 70 (HSP70) has emerged as an important player in vascular reactivity under physiological conditions via its interaction with calcium mobilization, and in T2D, blocking this protein prevents hypercontractility. Circulating extracellular HSP70 (eHSP70) has also been proposed as a biomarker in chronic diseases, as it can function as a damage-associated molecular pattern (DAMP) to activate the innate immune system and promote low-grade inflammation. Berberine (BBR), a natural alkaloid with anti-inflammatory properties, has been shown to attenuate vascular contraction by modulating intracellular calcium handling. Yet the link between HSP70 and BBR in modulating vascular contraction in T2D remains unknown. Therefore, we investigated whether acute and/or chronic BBR treatment modulates HSP70 to prevent vascular hypercontractility in the T2D mouse model. For acute ex vivo treatment, db/+ and db/db aortic rings were incubated for 30 min with or without the HSP70 inhibitor VER155008, in the presence or absence of BBR or vehicle. For chronic in vivo treatment, db/+ and db/db mice received intraperitoneal BBR injections (10 mg/kg, 3 times per week) and BBR in their drinking water (0.5 mg/mL) for 28 days. Following chronic (4 weeks, in vivo) or acute ex vivo (30 min) BBR treatment, vascular function was assessed in aortic rings isolated from male T2D (db/db) and age-matched non-diabetic (db/+) mice using wire myography. Rings were incubated with or without the HSP70 inhibitor VER155008, in the presence or absence of BBR or vehicle. Overt hyperglycemia and hypercontractility were observed in diabetic animals compared with non-diabetic controls. While acute BBR treatment attenuated vasoconstriction in both diabetic and nondiabetic groups, the combination of BBR and VER155008 produced a stronger inhibitory effect only in the diabetic group. Chronic BBR treatment prevented aortic hypercontractility in diabetic mice; however, the synergistic effect with VER155008 was no longer observed. Additionally, BBR reduced systemic HSP70 levels. Collectively, these findings indicate that BBR improves vascular smooth muscle cells’ function in T2D, at least in part, through HSP70-dependent mechanisms during chronic treatment. Full article

Bacillus thuringiensis Cry toxins are well known for their high insecticidal activity against Lepidoptera, Diptera, and Coleoptera and have been widely used in Bt transgenic crops. However, their activity against Hemipteran aphids remains relatively low. Identifying novel Cry proteins and elucidating their action mechanisms can facilitate the development of effective aphid control strategies. In this study, we found that ingestion of Cry2Ab12 did not kill Myzus persicae adults but significantly reduced their offspring number and exerted a lethal effect on M. persicae nymphs. After identifying Cry2Ab12 toxin-binding proteins in M. persicae, we further characterized the interaction with Obg-like ATPase 1 (OLA1), a conserved protein involved in growth regulation. Bio-layer interferometry (BLI), ELISA, and enzyme activity assays revealed that Cry2Ab12 and OLA1 do not interact directly. Interestingly, heat shock protein 60 (HSP60) was shown to mediate the interaction among Cry2Ab12, HSP60, and OLA1, leading to inhibition of OLA1 enzymatic activity. Based on these findings and bioinformatics simulations, we proposed a mechanistic model for Cry2Ab12 toxicity against M. persicae: upon ingestion of a sufficient amount of Cry2Ab12, the formation of the Cry2Ab12–HSP60–OLA1 complex impairs the cellular stress response, disrupts normal OLA1 expression, and ultimately restricts larval growth and development, resulting in lethality. This study provides new insights into the action of Cry toxins in aphids and offers a basis for developing enhanced aphid biocontrol strategies. Full article

Objectives: Neuroinflammation is recognized as a significant characteristic of Alzheimer’s disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation. Methods: In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism. Results: Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner. Conclusions: Maltol exhibits significant protective effects against Alzheimer’s disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer’s disease neuroinflammation using traditional Chinese medicine. Full article

Global freshwater salinization endangers aquatic species, yet its impacts on crustaceans remain poorly understood. This study investigated the hepatopancreatic response of Eriocheir sinensis to carbonate alkalinity stress (0, 4.375, 8.75, 17.5, and 35 mmol/L) over 24, 48, and 96 h, integrating histology, ultrastructure, gene expression (RT-qPCR), and non-specific immune enzyme assays. Histopathological and ultrastructural analyses revealed concentration- and time-dependent damage, including vacuolization, hepatic tubule disintegration, nuclear condensation, mitochondrial reduction, and loss of cellular integrity. Molecular analysis demonstrated upregulation of genes associated with the TLR2-MyD88-NF-κB pathway and inflammatory genes (LITAF, IL-16), alongside increased HSP70 expression, confirming severe inflammation and cellular stress. Furthermore, apoptosis was induced via upregulated Bax and Caspase-3, downregulated Bcl-2, and DNA fragmentation. Non-specific immune responses in the hepatopancreas exhibited dynamic changes: acid phosphatase (ACP) was initially activated at low alkalinity but inhibited at high concentrations, while alkaline phosphatase (AKP) activity increased at 96 h. Notably, the hepatopancreas proved more sensitive to this stress than the hemolymph. Collectively, carbonate alkalinity causes multidimensional hepatopancreatic injury in E. sinensis through structural disruption, inflammation mediated by TLR2-MyD88-NF-κB signaling pathway-related genes, apoptosis induction, and immune enzyme dysregulation, posing a significant threat to crab health in salinized waters. Full article

Background/Objectives: Tordylium trachycarpum Boiss. (Apiaceae) is traditionally used in Kurdish ethnomedicine for the management of gastrointestinal disorders; however, its pharmacological efficacy and safety profile remain insufficiently investigated. This study evaluated, for the first time, the gastroprotective activity and associated antioxidant, inflammatory, and apoptotic responses of the methanolic extract of T. trachycarpum using an ethanol-induced gastric ulcer model in Sprague–Dawley rats. Methods: Preliminary phytochemical screening revealed the presence of phenolics, flavonoids, terpenoids, tannins, coumarins, and glycosides. Acute oral toxicity testing demonstrated no signs of toxicity at doses up to 5 g/kg. Gastric ulceration was induced by absolute ethanol, and animals were pretreated with the extract (250 and 500 mg/kg) or omeprazole (20 mg/kg). Results: The extract significantly decreased the gastric lesion area from 258.50 ± 6.38 mm² in the ulcer control group to 143.70 ± 0.76 mm² and 115.50 ± 0.76 mm², corresponding to ulcer inhibition rates of 44.41% and 55.31%. Additionally, the extract increased mucus production, maintained mucosal structure, and raised stomach pH. Biochemical analysis showed a significant increase in antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] and a reduction in malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. In addition, the extract modulated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10). Blood-based ELISA analysis demonstrated increased expression of heat shock protein 70 (HSP70) and reduced Bax levels, suggesting anti-apoptotic activity. Conclusions: These findings indicate that T. trachycarpum exerts significant gastroprotective activity through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, supporting its traditional use and highlighting its potential as a natural therapeutic candidate for the management of gastric ulcers. Full article

The plastid stroma-localized chaperone HSP90C is essential for maintaining chloroplast proteostasis and facilitating protein translocation. Prior research has established HSP90C’s imperative role in the SEC translocase-dependent transport of the photosystem II subunit PsbO1 and its interaction with the SEC1 translocase motor protein SecA1. However, the exact mechanism of this interaction remains to be explored. In this study, we delineated the interactional mode of HSP90C and SecA1 with the model client protein. Yeast two-hybrid and in vitro ATPase activity analyses with purified proteins revealed PsbO1 may bind to HSP90C at multiple sites, including the DPW motif within the C-terminal extension (CTE) region, suggesting a possible client-loading mechanism unique to plastid orthologs. We also confirmed that glycine-646 is important in mediating substrate interaction, though it conferred a much weaker binding than the CTE region, thereby elucidating a critical role for the amino acid whose mutation resulted in visible plant phenotypes. Our in vitro biochemical assays also demonstrated that the stromal intermediate form of PsbO1 with the thylakoid signal peptide (tSP) significantly enhanced SecA1 ATPase activity, suggesting a preferential binding to the motor protein. On the other hand, the mature domain of the PsbO1, excluding the tSP sequence, inhibited HSP90C ATPase activity. We also observed the HSP90C-PsbO1-SecA1 ternary complex was stabilized by the presence of the client tSP. This work therefore provides new insights into the functional mechanisms of HSP90C and its contribution to chloroplast stromal protein stabilization and thylakoid protein transport. Full article

Gastric cancer remains a major clinical challenge, underscoring the need for more effective drug delivery strategies. Approximately 10–20% of gastric cancers overexpress HER2, conferring aggressive tumor characteristics and poor survival, yet resistance to trastuzumab-based targeted therapy and limited intratumoral antibody penetration continue to restrict clinical outcomes. This study evaluated HER2-targeted exosomes as a delivery platform. Exosomes were engineered to express the p51 peptide, a high-affinity HER2-binding ligand, and loaded with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a potent HSP90 inhibitor. The cellular uptake and antitumor efficacy of p51-Exo^17-DMAG were assessed in vitro using NCI-N87 and AGS cells and in vivo using a mouse xenograft model. p51-modified exosomes exhibited superior HER2 specific uptake. Treatment with p51-Exo^17-DMAG significantly increased apoptosis, as demonstrated by elevated PARP and caspase3 cleavage, and downregulated oncogenic signaling molecules, including p-AKT, CDK2, VEGF, and c-Myc. Furthermore, p51-Exo^17-DMAG increased the number of TUNEL-positive cells. In the NCI-N87 xenograft model, systemic administration of p51-Exo^17-DMAG significantly inhibited tumor growth without toxicity or histological damage to major organs. Tumor analysis confirmed increased apoptosis and reduced proliferation in vivo. These findings demonstrate that p51-engineered exosomes provide an efficient, selective, and safe platform for HER2-targeted delivery of 17-DMAG, offering a promising precision medicine strategy for HER2-positive gastric cancer. Full article

Heat shock protein 90 (HSP90) is a molecular chaperone essential for maintaining the stability of many oncogenic client proteins. Although several HSP90 inhibitors (HSP90i) have entered clinical trials, their use has been limited by toxicity and resistance, underscoring the need for improved therapeutic strategies. In this study, we assessed the therapeutic potential of a new HSP90i, SP11, in T-cell acute lymphoblastic leukemia (T-ALL) in vitro and in the DLA mouse model in vivo, using single-cell transcriptomic profiling. Single-cell RNA sequencing showed that SP11 treatment reduces key oncogenic drivers, including MYC, BCL2, and stemness-related genes, consistent with impaired leukemic survival programs. In the DLA mouse model, SP11-mediated HSP90 inhibition was associated with alterations in the tumor microenvironment, including increased immune cell representation and enrichment of cytokine- and antigen-presentation-related transcriptional pathways. Despite these antitumor effects, a distinct subpopulation of cells continued to express or re-express MYC and BCL2, suggesting the development of early adaptive resistance. Consistent with these findings, an SP11-resistant MOLT4 cell line maintained high levels of MYC and BCL2 at both the transcript and protein levels, maintained CD44 expression, and exhibited altered inflammatory cytokine signaling. Functional studies confirmed that pharmacological inhibition of BCL2 notably increased SP11 sensitivity, supporting a rational combination strategy. Collectively, our results show that SP11 may exert both tumor-intrinsic and immune-modulating effects and reveal transcriptionally defined adaptive cellular states linked to resistance. This study provides mechanistic in sights into responses to HSP90 inhibition and supports combination approaches for improving therapeutic outcomes in T-ALL. Full article

Allergic rhinitis (AR) is one of the most prevalent allergic disorders worldwide. Current pharmacological treatments are often limited by suboptimal efficacy and notable adverse effects. Herbal medicines, with their multi-component and multi-target therapeutic characteristics, have attracted increasing attention. Artemisia ordosica Krasch. (AOK), a traditional Chinese/Mongolian medicine has demonstrated immunomodulatory, antioxidant, and anti-inflammatory activities. The anti-AR potential of AOK extract fractions was evaluated using in vitro mast cell degranulation inhibition assays, network pharmacology analysis, molecular docking, and molecular dynamics simulations to elucidate underlying pharmacological mechanisms. The P815 mast cell model induced by compound 48/80 was employed to assess the inhibitory activity and cytotoxicity of different extract fractions. Among the tested fractions, the ethyl acetate fraction exhibited the most potent inhibitory effect on mast cell degranulation without significant cytotoxicity. Network pharmacology analysis identified 254 potential AR-related targets of AOK, with Signal Transducer and Activator of Transcription 3(STAT3), Src protein(SRC), Tumor protein 53(TP53), AKT Serine/Threonine Kinase 1(AKT1), Heat Shock Protein 90 Alpha Family Class A Member 1(HSP90AA1), Estrogen Receptor 1(ESR1), and Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA) identified as key hub proteins. Gene Ontology and KEGG pathway enrichment analyses indicated that AOK primarily modulated inflammatory and oxidative stress-related processes through the lipid and atherosclerosis, hypoxia-inducible factor-1, and AGE-RAGE signaling pathways. Molecular docking and dynamics simulations demonstrated strong binding affinities and stable interactions between major active constituents, particularly hydroxygenkwanin, and key targets such as SRC. The ethyl acetate fraction of AOK extract exhibited significant mast cell degranulation inhibitory activity, likely mediated via a synergistic multi-component, multi-target mechanism involving regulation of inflammatory and immune-related signaling pathways. These findings provide a pharmacological basis for the potential application of AOK in AR treatment. Full article

During development, stem cells rapidly proliferate and differentiate to form the embryo and the placenta, requiring intensive increases in cellular protein synthesis and changes to the cell architecture. Chaperone proteins, including the small heat shock proteins (HSPs), are critical assistants to protein folding, preventing protein aggregation, and promoting autophagy. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) is a stress-activated kinase that promotes fetal and placental growth. MAP3K4 directly activates p38 and JNK in trophoblast stem (TS) cells by phosphorylating MAP2K3 and MAP2K4/7, respectively. In addition, MAP3K4 promotes activation of the Akt signaling pathway by controlling Igf1r expression. TS cells differentiate to placental trophoblasts comprising the junctional zone (JZ) and labyrinth (LAB) placental layers. In this study, we demonstrate that JZ differentiation transiently increases JNK activity, whereas LAB differentiation induces sustained p38, JNK, and Akt activation. Each of these pathways is inhibited in MAP3K4 kinase-inactive (KI) LAB^KI trophoblasts. JZ and LAB differentiation also induces HSP22 and HSP27 expression and HSP27 phosphorylation; these are also reduced in TS^KI and LAB^KI cells. JZ and LAB differentiation induces GABARAP-positive autophagosomes that are deficient in KI cells. Altogether, our findings demonstrate that MAP3K4 is critical for responses during differentiation in placental trophoblasts. Full article

Objectives: This study aims to investigate the pharmacological effects and potential mechanisms of dehydrocorydaline, the primary active component of Corydalis yanhusuo W.T. Wang, as a potential therapeutic agent for pancreatic cancer, thereby providing new insights into its treatment. Methods: The pharmacological effects were assessed through MTT assay, colony formation assay, flow cytometry, scratch wound assay, and transwell assay. Potential mechanisms were explored through bioinformatics analysis and Western blot. Results: Dehydrocorydaline was verified to stimulate apoptosis and inhibit the growth, migration, and invasion of pancreatic cancer BxPC-3 cells. These effects may be associated with suppressed HSP90α expression, induced ERBB2 degradation, and subsequent inhibition of STAT3 and PI3K/Akt/mTOR pathway activation, as well as altered expression of multiple downstream proteins. Conclusions: This study demonstrates that dehydrocorydaline is the main active component of Corydalis yanhusuo W.T. Wang with anti-pancreatic cancer activity. Based on protein expression-level evidence, it may exert its effects by inhibiting HSP90α expression and inducing ERBB2 degradation, thereby affecting the PI3K/Akt/mTOR and STAT3 pathways, ultimately suppressing proliferation, migration, and invasion while promoting apoptosis in BxPC-3 cells. These findings justify further investigation of dehydrocorydaline as a potential treatment for pancreatic cancer. Full article

As the global average temperature increases, heat stress (HS) caused by high temperatures has become a key constraint to the development of the poultry industry. As the primary metabolic organ, HS can induce liver injury in chickens, thereby compromising feed safety. However, the precise mechanisms underlying HS-induced liver injury remain to be elucidated. The objective of this study is to explore the impact of HS on liver damage, oxidative stress, the Keap1-Nrf2 pathway, ferroptosis and cuproptosis in chickens. A total of 70 chickens were selected for this experiment and divided into a CON group and a HS group: the CON group was reared in a normal-temperature environment (24 ± 1°C), whilst the chronic HS group was reared in a high-temperature environment (33 ± 1°C). The findings of the study suggested that HS has the potential to induce liver dysfunction, oxidative stress, and disruption of the Keap1-Nrf2 pathway. HS has been demonstrated to induce Fe²⁺ accumulation in chicken livers, inhibit the expression of FTH1, FSP1, SLC7A11 and Gpx4, and simultaneously upregulate the expression of CD71, PTGS2 and ACSL4, thereby promoting ferroptosis. Furthermore, Cu²⁺ accumulation in the liver upregulates HSP70, DLAT and Lip-DLAT levels and downregulates the expression of ATP7B, PDH1A, PDHB, PDK4, DLST and FDX1, thereby inducing cuproptosis. Subsequent correlation analysis revealed that HS can induce ferroptosis and cuproptosis via the HO-1/FDX1/Gpx4 pathway. This finding provides new insights into the mechanisms underlying HS-induced liver injury. Full article

Myalgic Encephalomyelitis (ME) is a chronic, multisystem disease characterized by systemic metabolic dysfunction and post-exertional malaise (PEM). In this study, we investigated the dysregulation of irisin, an exercise-induced myokine, and its potential antagonism by thrombospondin-1 (TSP-1). In a cross-sectional study (92 ME patients vs. 44 sedentary healthy controls), plasma irisin and TSP-1 levels were measured at baseline and after a 90 min mechanical stress challenge applied to induce PEM. ME patients exhibited significantly lower baseline irisin (p < 0.05) and a blunted exertional response (p < 0.05). Paradoxically, baseline irisin was an independent predictor of fatigue severity (β = 0.728, p = 0.018), with moderate-to-severe patients showing elevated levels of both irisin and TSP-1 (p < 0.05), suggesting a compensatory but ineffective response. Functional cellular dielectric spectroscopy indicated that TSP-1 inhibits irisin signaling in a concentration-dependent manner. Irisin signaling was markedly reduced by both αvβ5 blockade and HSP90α inhibition in this experimental system, consistent with a diminished ability to counteract TSP-1. Collectively, these findings support a model in which dysregulation of the irisin–TSP-1 axis contributes to metabolic dysfunction in ME. Elevated circulating TSP-1 levels are associated with symptom severity and are linked to impaired irisin signaling in an HSP90α- and αvβ5-dependent context. This interaction is consistent with defective metabolic adaptation and highlights a potential therapeutic target that warrants further validation to restore energy homeostasis. Full article

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. Full article

Introduction: Heat shock proteins (HSPs) are stress-responsive molecular chaperones that are frequently dysregulated in cancer and contribute to tumorigenesis, invasion, metastasis, immune interactions, and resistance to therapy. Distinct HSP families, including HSP27, HSP60, HSP70, HSP90, and HSP110, promote malignant progression through complementary effects on apoptosis regulation, mitochondrial function, proteostasis, and stabilization of oncogenic signaling pathways. This makes HSPs attractive therapeutic targets. Their coordinated roles within stress-adaptive chaperone networks further garner interest in targeting multiple HSP families in cancer therapy. Discussion: Preclinical and clinical studies have established multiple HSP families as promising anticancer targets; however, clinical translation of HSP-directed therapies has been challenged by toxicity, compensatory heat shock responses, and resistance mechanisms. Many N-terminal HSP90 inhibitors have shown clinical utility but have also highlighted the need for alternative approaches, including C-terminal inhibition, HSP70-directed therapies, and rational combination strategies targeting compensatory survival pathways. Emerging inhibitors targeting HSP27, HSP60, and HSP110, as well as HSP-based vaccines, further expand therapeutic opportunities across cancer subtypes. Collectively, these approaches highlight the growing therapeutic relevance of disrupting interconnected HSP networks rather than targeting individual chaperones in isolation. Conclusions: Future development of heat shock protein-targeted therapies will require a deeper understanding of HSP-mediated chemoresistance. Clinical trial and drug development approaches may benefit from combination or multi-targeted strategies that simultaneously disrupt multiple components of the heat shock protein network to achieve more durable anticancer responses. Full article