HSF1 (Heat Shock Transcription Factor 1)

Activation of HSF1 in aged wild-type HSCs partially restores youthful features, supporting a causal role for proteostasis maintenance. Collectively, our findings demonstrate that attenuating MDA5-dependent inflammation preserves HSC function during aging by maintaining metabolic fitness and proteostasis and provide insight into potential therapeutic strategies for mitigating hematopoietic aging.

The differences between cell types need to be clarified. This study confirms that TRAP1 is a target of interest in breast cancer cells, but some of its functions still need to be elucidated.

Here, we assess how HSF1 activation influences mutational trajectories by which p53 can escape cytotoxic pressure from nutlin-3, an inhibitor of the p53 regulator mouse double minute 2 homolog (MDM2). HSF1 activation broadly increases the fitness of dominant-negative p53 substitutions, particularly non-conservative, biophysically unfavorable amino acid changes within buried regions of the p53 DNA-binding domain. These findings demonstrate that HSF1 activation reshapes the oncogenic mutational landscape by preferentially supporting the emergence and persistence of biophysically disruptive, cancer-associated p53 substitutions, linking proteostasis network activity directly to oncogenic evolution.

Furthermore, resveratrol reduced HSF1 expression by inducing a proteasome-mediated degradation. Our results provide the first evidence that resveratrol inhibits the EMT of cancer cells, which might be involved in the suppression of HSF1.

Together, these findings reveal proteostasis as a key constraint in the aging hematopoietic system that imposes a selective bottleneck. Hsf1 activation enables both physiological adaptation in aging stem cells and pathological clonal outgrowth in pre-leukemic and leukemic states, establishing proteostasis control as a pivotal mechanism linking stem cell aging to clonal hematopoiesis and malignancy.

The combination strategy showed synergistic and selective anti-tumor activity across a panel of cancer cell lines. This success relied on the distinct profile of C4, which preferentially targets cytosolic HSP70 and, unlike conventional inhibitors, effectively circumvents compensatory HSP70 upregulation.

Key developments include next-generation AR pathway inhibitors, such as darolutamide, with improved safety profiles; PARP inhibitors for patients with DNA repair gene mutations; and PSMA-targeted radioligand therapy. The therapeutic landscape is also expanding to include novel targets such as the heat shock response, with HSF1 inhibitors like NXP800 in clinical trials for treatment-refractory disease. By targeting this molecular heterogeneity, ongoing research aims to deliver more effective, personalized treatments to improve survival and quality of life for men with advanced prostate cancer.

Targeting HSF1 is sensitive to synergistic combination PARP inhibitor treatment in CRC. Therefore, our study provides a new approach to synergize PARP inhibitor for CRC therapy.

Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.

A naturally occurring bioactive substance, "celastrol," is extracted from the root of Tripterygium wilfordii Hook F. Its effectiveness can be enhanced with the support of nanotechnology to overcome its limitations in cancer treatment. However, the toxicity, dosage, and safety assessments of celastrol and nanocelastrol in cancer applications must be further investigated.

This study demonstrates a novel systems biology strategy for evaluating drug response in silico, leveraging transcriptomic data to simulate individual treatment outcomes and uncover clinically relevant biomarkers. Our findings suggest that such approaches may serve as valuable complements to traditional clinical trials for assessing drug efficacy and guiding precision oncology.

Our results highlight the critical role of HSF1 as a metastasis-promoting transcription factor and a novel regulatory mechanism of HSF1 activity and stability by DBC1. Thus, targeting the HSF1-DBC1 axis could be a promising therapeutic strategy for metastatic cancers.