Qinmiao Sun

Heat shock protein 90 (HSP90) is an evolutionarily conserved molecular chaperone that occupies a central position in cellular proteostasis and adaptation to stress. By promoting protein folding and facilitating the functional activation of a broad repertoire of clients, HSP90 underpins essential cellular processes, including development, proliferation, differentiation, and stress responses. In cancer, this extensive network renders tumor cells highly dependent on HSP90 to maintain oncogenic signaling, tolerate proteotoxic stress, and survive therapeutic insults. In this review, we propose an integrated conceptual framework linking HSP90's molecular chaperone functions to its pathological roles in cancer: HSP90 serves as a central node that concurrently supports oncogenic signaling, buffers proteotoxic stress, maintains cancer stem cell plasticity, and shapes tumor‐immune interactions‐all of which converge to drive therapeutic resistance and tumor recurrence. Within this framework, we summarize the molecular mechanisms governing HSP90 activity and dissect its context‐dependent roles in cancer progression, drug resistance, and immune regulation. We further highlight recent advances in HSP90‐targeted interventions, including small‐molecule inhibitors, monoclonal antibodies, engineered immune cells, and emerging strategies designed to prevent, delay, or overcome drug resistance. Taken together, these developments underscore HSP90 as a versatile therapeutic node and point toward innovative, resistance‐aware strategies for clinical translation and future research.

Zygotic genome activation (ZGA) marks the first transcriptional milestone and establishes embryonic totipotency. Although pioneer factors have been reported to initiate this process, how chromatin is primed for the totipotent state, allowing the binding of pioneer factors for successful ZGA, remains unclear. Here, we identify IntS11, the catalytic subunit of the Integrator complex, as a totipotent determinant of embryonic chromatin governing ZGA in Drosophila . We show that IntS11 functions upstream of pioneer factors in early embryos: Maternal IntS11 depletion substantially impairs RNA polymerase II (Pol II) recruitment, thereby preventing pioneer factors Zelda and GAGA factor (GAF) from accessing regulatory elements and initiating genome-wide zygotic transcription. Mechanistically, IntS11 exerts dual roles: its canonical endonuclease activity is required to sustain major-wave zygotic transcription, while a distinct enzyme-independent function drives de novo Pol II loading and pioneer factor engagement. These findings uncover a fundamental maternal-specific mechanism whereby IntS11 establishes transcriptional competence, ensuring totipotent chromatin states and successful ZGA.

Probiotic strains exhibiting bile salt hydrolase (BSH) activity represent a promising therapeutic strategy for ameliorating metabolic disorders via targeting the gut–liver axis. Herein, we characterized a newly isolated human-derived Enterococcus strain and investigated its therapeutic potential. Genomic analysis confirmed its safety profile, while in vitro assays demonstrated potent BSH activity. Subsequently, C57BL/6J mice fed a high-cholesterol diet were orally administered this strain over an eight-week intervention period. Although the treatment did not significantly reduce serum cholesterol levels, a marked reduction in hepatic lipid droplet accumulation was confirmed by H&E and Oil Red O staining. Mechanistically, the strain’s potent BSH activity likely modulates bile acid metabolism within the gut–liver axis, thereby specifically inhibiting hepatic lipid deposition. Comprehensive histopathological examination of major organs revealed no signs of toxicity, affirming its excellent in vivo safety profile. In summary, E. lactis IOBRA9746 constitutes a safe and BSH-active probiotic candidate, whose primary beneficial effect lies in directly alleviating hepatic lipid accumulation independent of systemic cholesterol modulation. These findings highlight its potential as a novel liver-targeted intervention for preventing metabolic diseases induced by suboptimal dietary patterns.

Acute myeloid leukemia (AML) is a heterogeneous malignancy with low survival rates, primarily due to its inherent complexity. This underscores the urgent need to identify specific targets for precision medicine. Here, multi‐omics approaches are utilized and discover that AML cells undergo chaperone‐mediated chronic endoplasmic reticulum (ER) stress. Through integrative analyses of single‐cell RNA‐seq, cell‐surface proteomes, and cellular biology, ER chaperone proteins (e.g., HSP90B1 and P4HB) are identified as potential neoantigens that translocate to the cell surface upon chronic ER stress. These results suggest that these proteins, especially in FLT3‐ITD ⁺ AML cells, show great promise as diagnostic markers and therapeutic targets. To explore the therapeutic potential, chimeric antigen receptor–natural killer (CAR‐NK) cells targeting surface‐localized HSP90B1 are engineered. These engineered cells show selective cytotoxicity both in vitro and in animal models. This study not only identifies neoantigens as specific biomarkers refining AML classification, but also emphasizes the potential of immunotherapy‐based precision treatments for AML.

Early embryos undergo profound changes in their genomic architecture to establish the totipotent state, enabling pioneer factors to access chromatin and drive zygotic genome activation (ZGA). However, the mechanisms by which the totipotent state is established and properly interpreted by pioneer factors to allow orderly ZGA remain unknown. Here, we identify the H3.3-specific chaperone HIRA as a factor involving establishing totipotent-state chromatin inDrosophilaearly embryos. Through cophase separation with HIRA, the pioneer factor GAGA factor (GAF) efficiently binds to H3.3-marked nucleosomes to activate major-wave zygotic genes. Importantly, dPCIF1, a chromatin-associated protein, antagonized the GAF–HIRA interaction by competitively binding to HIRA, thereby restricting GAF on earlier chromatin and avoiding premature ZGA. Hence, the coordinated action of HIRA and dPCIF1 ensures sequential ZGA from the minor to major wave in early embryos. This study provides insights into understanding how a totipotent state is established and properly controlled during ZGA.

Upstream open reading frames (uORFs) are critical cis -acting regulators of downstream gene expression. Specifically, uORFs regulate translation by disrupting translation initiation or mediating mRNA decay. We herein summarize the effects of several uORFs that regulate gene expression in microbes to illustrate the detailed mechanisms mediating uORF functions. Microbes are ideal for uORF studies because of their prompt responses to stimuli. Recent studies revealed uORFs are ubiquitous in higher eukaryotes. Moreover, they influence various physiological processes in mammalian cells by regulating gene expression, mostly at the translational level. Research conducted using rapidly evolving methods for ribosome profiling combined with protein analyses and computational annotations showed that uORFs in mammalian cells control gene expression similar to microbial uORFs, but they also have unique tumorigenesis-related roles because of their protein-encoding capacities. We briefly introduce cutting-edge research findings regarding uORFs in mammalian cells.

Aberrant activation of the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8 ⁺ T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8 ⁺ T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8 ⁺ T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology.

The cGAS‐STING signaling pathway plays a pivotal role in sensing cytosolic DNA and initiating innate immune responses against various threats, with disruptions in this pathway being associated with numerous immune‐related disorders. Therefore, precise regulation of the cGAS‐STING signaling is crucial to ensure appropriate immune responses. Recent research, including ours, underscores the importance of protein condensation in driving the activation and maintenance of innate immune signaling within the cGAS‐STING pathway. Consequently, targeting condensation processes in this pathway presents a promising approach for modulating the cGAS‐STING signaling and potentially managing associated disorders. In this review, we provide an overview of recent studies elucidating the role and regulatory mechanism of protein condensation in the cGAS‐STING signaling pathway while emphasizing its pathological implications. Additionally, we explore the potential of understanding and manipulating condensation dynamics to develop novel strategies for mitigating cGAS‐STING‐related disorders in the future.