bims-hisfre Biomed News
on HSF1 and Creatine
Issue of 2025–06–22
seven papers selected by
James Heilman, Oregon Health & Science University
  1. HSF1 Activation Mechanisms, Disease Roles, and Small Molecule Therapeutics.
  2. Regulation of NRF2 by Stably associated Phosphoinositides and Small Heat Shock Proteins in Response to Stress.
  3. Co-chaperones fine-tune the function of heat shock protein 70 (Hsp70), whether to fold, hold, or degrade substrates in ensuring cellular protein homeostasis.
  4. Heat shock proteins function as signaling molecules to mediate neuron-glia communication in C. elegans during aging.
  5. CHPG's role in regulating apoptosis in heat-stressed microglia through endoplasmic reticulum stress: A new perspective☆.
  6. Engineering small extracellular vesicles: Unlocking the brain's secret passage for central nervous system therapies.
  7. Proteostasis signatures in human diseases.
  1. Int J Biol Sci. 2025 ;21(8): 3351-3378
    HSF1 Activation Mechanisms, Disease Roles, and Small Molecule Therapeutics.
    Bingwei Zhang, Yumei Fan, Ke Tan.
      The heat shock factor 1 (HSF1) is a master transcription regulator that orchestrates the expression of heat shock proteins (HSPs) in response to various cellular stresses. Dysfunction of HSF1 contributes to the pathogenesis of a spectrum of acute and chronic diseases, including cancer. Consequently, the modulation of HSF1 activity through the development of small molecules emerges as a promising therapeutic strategy for disease treatment. The activation of HSF1 is a multifaceted process, governed by a complex interplay of regulatory mechanisms, including post-translational modifications, protein-protein interactions, and a balance between its activation and inactivation. Recently, a plethora of compounds, ranging from synthetic to naturally derived, that either inhibit or activate HSF1 was identified, holding considerable potential for the treatment of numerous human diseases. In this comprehensive review, we elucidate the sophisticated mechanisms underlying activation of human HSF1, introduce its role in the etiology of diseases, and provide a comprehensive summary of the inhibitors and activators of HSF1 that have been discovered to date. This review not only offers novel insights for the development of small molecule therapeutics targeting HSF1 but also charts new territories in the design of innovative interventions for the amelioration of disease.
    Keywords:  HSF1; activators; cancer; inhibitors; therapeutic strategy
    DOI:  https://doi.org/10.7150/ijbs.110447
  2. J Biol Chem. 2025 Jun 12. pii: S0021-9258(25)02217-3. [Epub ahead of print] 110367
    Regulation of NRF2 by Stably associated Phosphoinositides and Small Heat Shock Proteins in Response to Stress.
    Changliang Chen, Noah D Carrillo, Mo Chen, Tianmu Wen, Poorwa Awasthi, Richard A Anderson, Vincent L Cryns.
      Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase γ (PIPKIγ), which binds NRF2 and is required to stably couple phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to NRF2 in response to oxidative stress. Stress also induces the interaction of the small heat shock protein HSP27 and NRF2 and this interaction is enhanced by PtdIns(4,5)P2. Silencing PIPKIγ or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected collaboration between phosphoinositides, which are stably coupled to NRF2, and HSP27, which is recruited to NRF2 by a phosphoinositide-dependent mechanism to regulate NRF2 stability and function. These findings also point to PIPKIγ and HSP27 as drug targets to destabilize NRF2 in cancer.
    Keywords:  NRF2; PtdIns(4,5)P(2); nucleus; phosphoinositide; small heat shock proteins: oxidative stress
    DOI:  https://doi.org/10.1016/j.jbc.2025.110367
  3. J Biosci. 2025 ;pii: 48. [Epub ahead of print]50
    Co-chaperones fine-tune the function of heat shock protein 70 (Hsp70), whether to fold, hold, or degrade substrates in ensuring cellular protein homeostasis.
    Pramit Bhattacharjee, Joydeep Roy, Atin Kumar Mandal.
      The molecular chaperone Hsp70 is a pivotal player in cellular protein quality control due to its wide range of substrates ranging from unfolded, native, to misfolded proteins. Increasing evidence suggests that Hsp70 decides the fate of proteins; however, the inherent rules that govern the decision-making capacity of Hsp70 are not clear. In this review, we have articulated the functions of Hsp70 with respect to proteostasis and established a link between its co-chaperones in deciding the fate of the substrate. The substrate binding of Hsp70 is mediated by its catalytic cycle where Hsp70 achieves high- and low-substrate-affinity ADP- and ATP-bound forms, respectively. This catalytic cycle of Hsp70 is maintained by co-chaperones J-domain proteins (JDPs), and nucleotide exchange factors (NEFs). JDPs bind to the ATP-bound form of Hsp70 and hydrolyze ATP that enhances substrate binding, whereas NEFs exchange ADP with ATP and facilitate substrate release. During evolution, several isoforms of Hsp70 and its co-chaperones have emerged which may have functional significance. Apart from facilitating the catalytic cycle of Hsp70, co-chaperones often mediate collaboration between Hsp70 and downstream protein quality-control pathways such as the ubiquitin proteasome system, autophagy, or disaggregase machinery. Therefore, co-chaperones have a significant role in Hsp70's triage decision of whether to fold, hold, or degrade.
  4. Nat Neurosci. 2025 Jun 18.
    Heat shock proteins function as signaling molecules to mediate neuron-glia communication in C. elegans during aging.
    Jieyu Wu, Victoria R Yarmey, Olivia Jiaming Yang, Erik J Soderblom, Adriana San-Miguel, Dong Yan.
      The nervous system is primarily composed of neurons and glia, and the communication between them has profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted signals through ligand-receptor interactions on the cell membrane. Here we show a new mechanism for neuron-glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ of Caenorhabditis elegans, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the cross-talk between neurons and glia. We demonstrate that early aged neurons can transmit heat shock proteins to glia via extracellular vesicles. These neuronal heat shock proteins activate the glial IRE1-XBP1 pathway, leading to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a new mechanism for neuron-glia communication in the nervous system and provide new insights into our understanding of brain aging.
    DOI:  https://doi.org/10.1038/s41593-025-01989-0
  5. IBRO Neurosci Rep. 2025 Jun;18 823-829
    CHPG's role in regulating apoptosis in heat-stressed microglia through endoplasmic reticulum stress: A new perspective☆.
    Yan-Xuan He, Zhi-Qiang Zhang, Xin-Xin Zheng, Fan Huang, Guoxin He, Xi-Chong Yu, An-Cong Xu.
       Objective: This study aims to explore the influence of microglia-mediated endoplasmic reticulum (ER) stress on cell apoptosis during heat stroke. Understanding this is important as it may help develop new therapies for heat-induced cellular damage and protect glial cells and brain health.
    Methods: BV-2 cells were used as a cell model for this study. The negative control group was kept at 37°C throughout the experiment. Cells in the experimental group were pretreated with 1 mM CHPG (a selective mGluR5 agonist) for 0.5 hours, followed by heat shock (HS) for 0.5 hours at 40°C and then further cultivation at 37°C for 12 hours. The positive control cells underwent same condition except for drug pretreatment. Several assays were used including CCK8 assay for cell viability, flow cytometry for cell apoptosis index, immunofluorescence for the expression of GRP78, CHOP, and Caspase-12, as well as Western blotting for detecting the protein expression level of GRP78, CHOP, and Caspase-12.
    Results: Heat shock induced a significant release of endoplasmic reticulum-related proteins and increased the expression levels of GRP78, CHOP, and Caspase-12 in BV-2 cells. CHPG was found to inhibit endoplasmic reticulum stress and cell apoptosis.
    Conclusion: CHPG may primarily participate in heat shock by mediating endoplasmic reticulum stress and affecting microglia apoptosis.
    Keywords:  Apoptosis; CHPG; Endoplasmic reticulum stress; Heat stress; Microglia
    DOI:  https://doi.org/10.1016/j.ibneur.2025.05.011
  6. J Cereb Blood Flow Metab. 2025 Jun 19. 271678X251348816
    Engineering small extracellular vesicles: Unlocking the brain's secret passage for central nervous system therapies.
    Jing Zhou, Yanjin Pu, Xueqi Ren, Lingjie Li, Zhong Chen, Eng H Lo, Wenlu Li.
      Small extracellular vesicles (sEVs), naturally occurring extracellular vesicles, play a pivotal role in intercellular communication and have gained significant attention for their potential in treating central nervous system (CNS) diseases. Due to their ability to cross the blood-brain barrier (BBB) and deliver therapeutic cargo, sEVs are considered a promising vehicle for targeted drug delivery in CNS disorders. Recent advancements in sEVs engineering-such as surface modifications, genetic alterations, and cargo optimization-have substantially enhanced their specificity and therapeutic efficacy. This review examines the relevance of endogenous sEVs in CNS and highlights recent developments in sEVs engineering and cargo optimization. We then discuss strategies for targeting specific brain cells, including neurons, microglia, and endothelial cells. Although clinical applications show promising potential, they remain in early stages, with challenges including large-scale production, precise tracking, standardized preparation, and efficient long-distance targeting. Further research into the cellular mechanisms of sEVs -mediated delivery and the functional differences between sEVs derived from various cell types is crucial for advancing their clinical translation in CNS therapies.
    Keywords:  Central nervous system diseases; cell targeting; drug delivery; endogenous small extracellular vesicles; engineering small extracellular vesicles
    DOI:  https://doi.org/10.1177/0271678X251348816
  7. PLoS Comput Biol. 2025 Jun;21(6): e1013155
    Proteostasis signatures in human diseases.
    Christine M Lim, Michele Vendruscolo.
      The protein homeostasis (proteostasis) network maintains the proteome in a functional state. Although this network has been comprehensively mapped, its perturbations in disease remain incompletely characterised. To address this problem, here we define the proteostasis signatures, which represent the characteristic patterns of change in the proteostasis network associated with disease. We performed a large-scale, pan-disease analysis across 32 human diseases spanning 7 disease types. We first identified unique proteostasis perturbations in specific disease states. We then uncovered distinctive signatures differentiating disease types, pointing to a range of proteostasis mechanisms in disease development. Next, we tracked the temporal evolution of proteostasis signatures, revealing shifts in proteostasis disruption over the course of disease progression. Finally, we demonstrated how smoking, a major risk factor for many diseases, impairs proteostasis in a manner similar to disease, potentially creating a predisposed environment for disease onset. These results illustrate the opportunities offered by the study of human diseases from the perspective of proteostasis signatures.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013155
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