The role of proteomic instability in cancer, particularly amyloidogenesis, remains obscure. Heat shock factor 1 (HSF1) transcriptionally governs the proteotoxic stress response to suppress proteomic instability and enhance survival. Paradoxically, HSF1 promotes oncogenesis. Here, we report that AKT activates HSF1 via Ser²³⁰ phosphorylation. In vivo, HSF1 enables megalencephaly and hepatomegaly, which are driven by hyperactive phosphatidylinositol 3-kinase/AKT signaling. Hsf1 deficiency exacerbates amyloidogenesis and elicits apoptosis, thereby countering tissue overgrowth. Unexpectedly, HSF1 physically neutralizes soluble amyloid oligomers (AOs). Beyond impeding amyloidogenesis, HSF1 shields HSP60 from direct assault by AOs, averting HSP60 destabilization, collapse of the mitochondrial proteome, and, ultimately, mitophagy and apoptosis. The very same mechanism occurs in Alzheimer’s disease. These findings suggest that amyloidogenesis may be a checkpoint mechanism that constrains uncontrolled growth and safeguards tissue homeostasis, congruent with its emerging tumor-suppressive function. HSF1, by acting as an anti-amyloid factor, promotes overgrowth syndromes and cancer but may suppress neurodegenerative disorders.

Cadmium toxicity has been associated with disruption of protein homeostasis by interfering with protein folding processes. Heat shock factor 1 (HSF1) coordinates the rapid and extensive cellular response to maintain proteomic balance facing the challenges from many environmental stressors. Thus, we suspect that HSF1 may shield cells from cadmium toxicity by conserving proteome integrity. Here, we demonstrate that cadmium, a highly poisonous metal, induces aggregation of cytosolic proteins in human cells, which disrupts protein homeostasis and activates HSF1. Cadmium exposure increases HSF1's phosphorylation, nuclear translocation and DNA bindings. Aside from this, HSF1 goes through liquid-liquid phase separation to form small nuclear condensates upon cadmium exposure. A specific regulatory domain of HSF1 is critical for HSF1's phase separation capability. Most importantly, human cells with impaired HSF1 are sensitized to cadmium, however, cells with overexpressed HSF1 are protected from cadmium toxicity. Overexpression of HSF1 in human cells reduces protein aggregates, amyloid fibrils and DNA damages to antagonize cadmium toxicity. HSF1 protects cells from cadmium toxicity by governing the integrity of both proteome and genome. Similar mechanisms may enable HSF1 to alleviate cellular toxicity caused by other heavy metals. HSF1's role in cadmium exposure may provide important insights into the toxic effects of heavy metals on human cells and body organs, allowing us to better manage heavy metal poisoning.

RAS/MAPK signaling responds to diverse extracellular cues and regulates a wide array of cellular processes. Given its biological importance, abnormalities in RAS/MAPK signaling cascade have been intimately implicated in numerous human diseases, including cancer. Herein, we describe a novel methodology to study activation of this pivotal signaling pathway. The Proximity Ligation Assay (PLA) is employed to monitor kinase–substrate interactions between MEK1 and HSF1, or MEK1 and ERK1 in situ.

R-loops, three-stranded nucleic acid structures comprising an RNA-DNA hybrid and a displaced single-stranded DNA strand, play context-dependent roles in cancer—serving essential physiological functions while also driving tumorigenesis when dysregulated. Their pathological effects are mediated through replication stress, genomic instability, transcriptional disruption, and defective RNA processing. This review highlights the emerging potential of targeting R-loops as a therapeutic strategy in oncology. We survey advanced methodologies for R-loop mapping, addressing technical limitations of current approaches, and advocate for multi-omics integration to elucidate R-loop dynamics and functional networks in cancers such as lung, bladder, and prostate malignancies. Critically, we explore two promising therapeutic avenues: (1) direct inhibition of R-loop resolvers to trigger excessive R-loop accumulation and replication catastrophe, and (2) synthetic lethality strategies that capitalize on cancer-specific R-loop handling defects. Clinical evidence supporting these approaches is discussed, along with challenges including tumor heterogeneity, detection limitations, and adaptive resistance. We argue that a multi-omics-driven understanding of R-loop biology will accelerate the translation of R-loop-directed therapies into precision oncology.