LncRNA SNHG1 facilitates colorectal cancer cells metastasis by recruiting HNRNPD protein to stabilize SERPINA3 mRNA.

Metastasis continues to negatively impact individuals diagnosed with colorectal cancer (CRC). Research has revealed the important role of long noncoding RNAs (lncRNAs) in CRC metastasis, but the underlying mechanisms remain unclear. Here, we revealed that the lncRNA small nucleolar RNA host gene 1 (SNHG1) is expressed at higher levels in metastatic CRC tissues than in primary CRC tissues, and that high lncRNA SNHG1 expression indicates poor patient outcomes. We found that lncRNA SNHG1 promotes the migration and invasion of tumor cells both in vivo and in vitro. Moreover, lncRNA SNHG1 increases serpin family A member 3 (SERPINA3) mRNA stability by interacting with the heterogeneous nuclear ribonucleoprotein D (HNRNPD) protein, and subsequently upregulates SERPINA3 expression. Moreover, HNRNPD and SERPINA3 reversed the effects of lncRNA SNHG1 knockdown on CRC cell metastasis. In conclusion, we report that the lncRNA SNHG1 recruits HNRNPD, in turn upregulating SERPINA3 expression and ultimately facilitating CRC cell migration and invasion. Targeting the lncRNA SNHG1/HNRNPD/SERPINA3 signaling pathway might be a therapeutic option for preventing CRC metastasis.

Proteolysis targeting chimera extracellular vesicles for therapeutic development treating triple negative breast cancer.

Proteolysis targeting chimeras (PROTACs) are an emerging targeted cancer therapy approach, but wide-spread clinical use of PROTAC is limited due to poor cell targeting and penetration, and instability in vivo. To overcome such issues and enhance the in vivo efficacy of PROTAC drugs, microfluidic droplet-based electroporation (µDES) was developed as a novel extracellular vesicle (EVs) transfection system, which enables the high-efficient PROTAC loading and effective delivery in vivo. Our previously developed YX968 PROTAC drug had shown the selectively degradation of HDAC3 and 8, which effectively suppresses the growth of breast tumor cell lines, including MDA-MB-231 triple negative breast cancer (TNBC) line, via dual degradation without provoking a global histone hyperacetylation. In this study, we demonstrated that µDES-based PROTAC loading in EVs significantly enhanced therapeutic function of PROTAC drug in vivo in the TNBC breast tumor mouse model. NSG mice with pre-established MDA-MB-231 tumors and treated with intraperitoneal injection of EVs for tumor inhibition study, which showed significantly higher HDAC 3 and 8 degradation efficiency and tumor inhibition than PROTAC only group. The liver, spleen, kidney, lung, heart, and brain were collected for safety testing, which exhibited improved toxicity. The EV delivery of PROTAC drug enhances drug stability and bioavailability in vivo, transportability, and drug targeting ability, which fills an important gap in current development of PROTAC therapeutic functionality in vivo and clinical translation. This novel EV-based drug transfection and delivery strategy could be applicable to various therapeutics for enhancing in vivo delivery, efficacy, and safety.

Role of N6-methyladenosine RNA modification in cancer.

N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer-associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism-associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.

Enhanced bioremediation of soils contaminated with nicosulfuron using the bacterial complex A12.

AIMS: To construct an efficient bacterial complex to degrade nicosulfuron and clarify its degradative characteristics, promote the growth of maize (Zea mays), and provide a theoretical foundation for the efficient remediation of soil contaminated with nicosulfuron. METHODS AND RESULTS: Biocompatibility was determined by the filter paper sheet method by mixing Serratia marcescens A1 and Bacillus cereus A2 in a 1:1 ratio, yielding A12. The optimum culture conditions for the bacterial composite were obtained based on a three-factor, three-level analysis using response surface methodology, with 29.25 g l-1 for maltodextrin, 10.04 g l-1 for yeast extract, and 19.93 g l-1 for NaCl, which resulted in 92.42% degradation at 4 d. The degradation characteristics of A12 were clarified as follows: temperature 30°C, pH 7, initial concentration of nicosulfuron 20 mg l-1, and 4% inoculum. The ability to promote growth was determined by measuring the ratio of the lysosphere diameter (D) to the colony diameter (d), and the ability of the complex A12 to promote growth was higher than that of the two single strains. CONCLUSIONS: Nicosulfuron degradation in sterilized and unsterilized soils reached 85.4% and 91.2% within 28 d, respectively. The ability of the strains to colonize the soil was determined by extraction of total soil DNA, primer design, and gel electrophoresis. The bioremediation effect of A12 was confirmed by the maximum recovery of fresh weight (124.35%) of nicosulfuron-sensitive crop plants and the significant recovery of soil enzyme activities, as measured by the physiological indices in the sensitive plants.

Strengthening bioremediation potential: Enterobacter ludwigii ES2 for combined nicosulfuron and Cd contamination through whole genome and microbial diversity community analysis.

Nicosulfuron and Cd are common pollutants that pose significant threats to the environment and human health, particularly under combined stress. This study is the first to remediate environmental nicosulfuron and Cd under combined stress using microbiological techniques. Enterobacter ludwigii ES2 was isolated, characterized, and demonstrated to degrade 93.80 % of nicosulfuron and remove 59.64 % of Cd within 4 d. Potential functional genes, including nicosulfuron degradation genes gstA, gstB, glnQ, glnP, mreB, and sixA, and Cd tolerance/removal-related genes mntA, mntB, mntH, dnaK, znuA, and zupt, were predicted by sequencing the whole genome of strain ES2, and their expression was verified by qRT-PCR. Strain ES2 managed oxidative stress induced by Cd through superoxide dismutase, glutathione, catalase, peroxidase, and malondialdehyde. Furthermore, to repair compound stress, up to 90.48 % of nicosulfuron and 67.74 % of Cd were removed. The community structure analysis indicated that Enterobacteriaceae, Sphingomonadaceae, and Gemmatimonadaceae were dominant populations, with ES2 stably colonizing and becoming the dominant bacterium. In summary, ES2 demonstrated significant potential in remediating nicosulfuron and Cd pollution from various perspectives, providing a solid theoretical foundation.

GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma.

Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.

Radioactive sources search method based on multi-robot and Voronoi partition.

In this paper, it is proposed to locate multiple unknown radioactive sources within a certain time limit through particle filtering and Voronoi partitioning. Firstly, with each robot as a Voronoi centroid, the entire area is partitioned. Then, the robots conduct source search concurrently through particle filtering. When all the robots complete the process of one-particle filtering, the iteration ends and the next one begins until the search for the radioactive source is terminated. Finally, experiment is conducted to demonstrate the efficiency and accuracy of the proposed method.

A novel strategy for improving bowel preparation based on social software-enhanced education: A prospective, multicenter, randomized controlled study.

BACKGROUND AND AIM: The compliance and timeliness of oral laxatives have always been the key factors restricting bowel preparation (BP). We have constructed a novel enhanced-educational content and process based on social software (SS) for BP to optimize these issues. METHODS: A multicenter, prospective, randomized controlled study was conducted at 13 hospitals in China from December 2019 to December 2020. A total of 1774 enrollees received standard instructions for BP and were randomly assigned (1:1) to the SS group (SSG) that received a smartphone-based enhanced-education strategy starting 4 h before colonoscopy or the control group (CG). RESULTS: A total of 3034 consecutive outpatient colonoscopy patients were assessed for eligibility, and 1774 were enrolled and randomly assigned. Ultimately, data from 1747 (SSG vs CG: 875 vs 872) enrollees were collected. The BP adequacy rate was 92.22% (95% CI: 90.46-93.98) in the SSG vs 88.05% (95% CI: 85.91-90.18) in the CG (P = 0.005), and the total Boston Bowel Preparation Scale scores (6.89 ± 1.15 vs 6.67 ± 1.15, P < 0.001) of those in the SSG were significantly higher than those in the CG. The average number of polyps detected in the SSG was considerably higher than that in the CG (0.84 ± 2.00 vs 0.53 ± 1.19, P = 0.037), and the average diameter of the polyps was significantly lower than that of the control group (4.0 ± 2.5 vs 4.9 ± 3.7, P < 0.001). CONCLUSIONS: This SS-enhanced education strategy can improve the BP adequacy rate and increase the average number of polyps detected, especially those of small diameter.

Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging.

GPR84 is a promising therapeutic target and biomarker for a range of diseases. In this study, we reported the discovery of BINOL phosphate (BINOP) derivatives as GPR84 antagonists. By investigating the structure-activity relationship, we identified 15S as a novel GPR84 antagonist. 15S exhibits low nanomolar potency and high selectivity for GPR84, while its enantiomer 15R is less active. Next, we rationally designed and synthesized a series of GPR84 fluorogenic probes by conjugating Nile red and compound 15S. The leading hybrid, probe F8, not only retained GPR84 activity but also exhibited low nonspecific binding and a turn-on fluorescent signal in an apolar environment. F8 enabled visualization and detection of GPR84 in GPR84-overexpressing HEK293 cells and lipopolysaccharide-stimulated neutrophils. Furthermore, we demonstrated that F8 can detect upregulated GPR84 protein levels in mice models of inflammatory bowel disease and acute lung injury. Thus, compound F8 represents a promising tool for studying GPR84 functions.

Targeted Protein Degradation: Current and Emerging Approaches for E3 Ligase Deconvolution.

Targeted protein degradation (TPD), including the use of proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) to degrade proteins, is an emerging strategy to develop novel therapies for cancer and beyond. PROTACs or MGDs function by inducing the proximity between an E3 ligase and a protein of interest (POI), leading to ubiquitination and consequent proteasomal degradation of the POI. Notably, one major issue in TPD is the lack of ligandable E3 ligases, as current studies predominantly use CUL4CRBN and CUL2VHL. The TPD community is seeking to expand the landscape of ligandable E3 ligases, but most discoveries rely on phenotypic screens or serendipity, necessitating systematic target deconvolution. Here, we examine and discuss both current and emerging E3 ligase deconvolution approaches for degraders discovered from phenotypic screens or monovalent glue chemistry campaigns, highlighting future prospects for identifying more ligandable E3 ligases.

Discovery of a Highly Potent and Selective HDAC8 Degrader: Advancing the Functional Understanding and Therapeutic Potential of HDAC8.

HDAC8 plays crucial roles in biological processes, from gene regulation to cell motility, making it a highly desirable target for therapeutic intervention. HDAC8 also has deacetylase-independent activity which cannot be blocked by a conventional inhibitor. In this study, we report the discovery of YX862, a highly potent and selective hydrazide-based HDAC8-proteolysis targeting chimera (PROTAC) degrader. The selectivity is achieved through rational design of the warhead to spare HDAC3 activity from the previous HDAC3/8 dual degrader YX968. We demonstrate that the degradation of HDAC8 by YX862 increases acetylation levels of its nonhistone substrates such as SMC3 without significantly triggering histone PTM, supporting HDAC8's major role in nonhistone PTM regulation. YX862 exhibits promising on-target antiproliferative activity against DLBCL cells with higher potency than the HDAC8 selective inhibitor PCI-34051. As a selective HDAC8 degrader that avoids pan-HDAC inhibition, YX862 represents a valuable tool for exploring the biological and therapeutic potential of HDAC8.

A new artificial intelligence system for both stomach and small-bowel capsule endoscopy.

BACKGROUND AND AIMS: Despite the benefits of artificial intelligence in small-bowel (SB) capsule endoscopy (CE) image reading, information on its application in the stomach and SB CE is lacking. METHODS: In this multicenter, retrospective diagnostic study, gastric imaging data were added to the deep learning-based SmartScan (SS), which has been described previously. A total of 1069 magnetically controlled GI CE examinations (comprising 2,672,542 gastric images) were used in the training phase for recognizing gastric pathologies, producing a new artificial intelligence algorithm named SS Plus. A total of 342 fully automated, magnetically controlled CE examinations were included in the validation phase. The performance of both senior and junior endoscopists with both the SS Plus-assisted reading (SSP-AR) and conventional reading (CR) modes was assessed. RESULTS: SS Plus was designed to recognize 5 types of gastric lesions and 17 types of SB lesions. SS Plus reduced the number of CE images required for review to 873.90 (median, 1000; interquartile range [IQR], 814.50-1000) versus 44,322.73 (median, 42,393; IQR, 31,722.75-54,971.25) for CR. Furthermore, with SSP-AR, endoscopists took 9.54 minutes (median, 8.51; IQR, 6.05-13.13) to complete the CE video reading. In the 342 CE videos, SS Plus identified 411 gastric and 422 SB lesions, whereas 400 gastric and 368 intestinal lesions were detected with CR. Moreover, junior endoscopists remarkably improved their CE image reading ability with SSP-AR. CONCLUSIONS: Our study shows that the newly upgraded deep learning-based algorithm SS Plus can detect GI lesions and help improve the diagnostic performance of junior endoscopists in interpreting CE videos.

Insights into the role of RNA m6A modification in the metabolic process and related diseases.

According to the latest consensus, many traditional diseases are considered metabolic diseases, such as cancer, type 2 diabetes, obesity, and cardiovascular disease. Currently, metabolic diseases are increasingly prevalent because of the ever-improving living standards and have become the leading threat to human health. Multiple therapy methods have been applied to treat these diseases, which improves the quality of life of many patients, but the overall effect is still unsatisfactory. Therefore, intensive research on the metabolic process and the pathogenesis of metabolic diseases is imperative. N6-methyladenosine (m6A) is an important modification of eukaryotic RNAs. It is a critical regulator of gene expression that is involved in different cellular functions and physiological processes. Many studies have indicated that m6A modification regulates the development of many metabolic processes and metabolic diseases. In this review, we summarized recent studies on the role of m6A modification in different metabolic processes and metabolic diseases. Additionally, we highlighted the potential m6A-targeted therapy for metabolic diseases, expecting to facilitate m6A-targeted strategies in the treatment of metabolic diseases.

Modification patterns and metabolic characteristics of m6A regulators in digestive tract tumors.

M6A is essential for tumor occurrence and progression. The expression patterns of m6A regulators differ in various kinds of tumors. Transcriptomic expression statistics together with clinical data from a database were analyzed to distinguish patients with digestive tract tumors. Based on the expression patterns of diverse m6A regulators, patients were divided into several clusters. Survival analysis suggested significant differences in patient prognosis among the m6A clusters. The results showed overlapping of m6A expression patterns with energy metabolism and nucleotide metabolism. Functional analyses imply that m6A modifications in tumor cells probably drive metabolic reprogramming to sustain rapid proliferation of cancer cells. Our analysis highlights the m6A risk characterizes various kinds of metabolic features and predicts chemotherapy sensitivity in digestive tract tumors, providing evidence for m6A regulators as markers to predict patient outcomes.

PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

Plasma and urine proteomics and gut microbiota analysis reveal potential factors affecting COVID-19 vaccination response.

The efficacy of COVID-19 vaccination relies on the induction of neutralizing antibodies, which can vary among vaccine recipients. In this study, we investigated the potential factors affecting the neutralizing antibody response by combining plasma and urine proteomics and gut microbiota analysis. We found that activation of the LXR/FXR pathway in plasma was associated with the production of ACE2-RBD-inhibiting antibodies, while urine proteins related to complement system, acute phase response signaling, LXR/FXR, and STAT3 pathways were correlated with neutralizing antibody production. Moreover, we observed a correlation between the gut microbiota and plasma and urine proteins, as well as the vaccination response. Based on the above data, we built a predictive model for vaccination response (AUC = 0.85). Our study provides insights into characteristic plasma and urine proteins and gut microbiota associated with the ACE2-RBD-inhibiting antibodies, which could benefit our understanding of the host response to COVID-19 vaccination.

Comparative chloroplast genome analyses provide insights into evolutionary history of Rhizophoraceae mangroves.

Background: The Rhizophoraceae family comprises crucial mangrove plants that inhabit intertidal environments. In China, eight Rhizophoraceae mangrove species exist. Although complete chloroplast (Cp) genomes of four Rhizophoraceae mangrove plants have been reported, the Cp genomes of the remaining four species remain unclear, impeding a comprehensive understanding of the evolutionary history of this family. Methods: Illumina high-throughput sequencing was employed to obtain the DNA sequences of Rhizophoraceae species. Cp genomes were assembled by NOVOPlasty and annotated using CpGAVAS software. Phylogenetic and divergence time analyses were conducted using MEGA and BEAST 2 software. Results: Four novel Cp genomes of Rhizophoraceae mangrove species (Bruguiera sexangula, Bruguiera gymnorrhiza, Bruguiera × rhynchopetala and Rhizophora apiculata) were successfully assembled. The four Cp genomes ranged in length from 163,310 to 164,560 bp, with gene numbers varying from 124 to 128. The average nucleotide diversity (Pi) value of the eight Rhizophoraceae Cp genomes was 0.00596. Phylogenetic trees constructed based on the complete Cp genomes supported the monophyletic origin of Rhizophoraceae. Divergence time estimation based on the Cp genomes of representative species from Malpighiales showed that the origin of Rhizophoraceae occurred at approximately 58.54-50.02 million years ago (Mya). The divergence time within the genus Rhizophora (∼4.51 Mya) was much earlier than the divergence time within the genus Bruguiera (∼1.41 Mya), suggesting recent speciation processes in these genera. Our data provides new insights into phylogenetic relationship and evolutionary history of Rhizophoraceae mangrove plants.

Antifungal activity of Klebsiella grimontii DR11 against Fusarium oxysporum causing soybean root rot.

AIMS: Soybean root rot, caused by Fusarium oxysporum, leads to significant economic and financial losses to the soybean processing industry globally. In the study, we aimed to explore a biocontrol agent to combat F. oxysporum infection in soybean. METHODS AND RESULTS: From soybean rhizosphere soil, 48 strains were isolated. Among them, the strain DR11 exhibited the highest inhibition rate of 72.27%. Morphological, physiological, biochemical, and 16S rDNA identification revealed that the strain DR11 was Klebsiella grimontii DR11. Strain DR11 could inhibit the growth of F. oxysporum and spore formation and alter the mycelial morphology. At 5.0 × 106 CFU mL-1, pH 7, and 30°C, it exhibited the highest inhibitory rate (72.27%). Moreover, it could decrease the activity of cell-wall-degrading enzymes of F. oxysporum. Simultaneously, the activities of defense-related enzymes and content of malondialdehyde in soybean plants were increased after treatment with strain DR11. In addition, strain DR11 could form aggregates to form biofilm and adsorb on the surface of soybean roots. It inhibited F. oxysporum growth on soybean seedlings, with an inhibitory effect of 62.71%. CONCLUSION: Klebsiella grimontii DR11 had a strong inhibitory effect on F. oxysporum and could be used as a biocontrol agent to combat F. oxysporum infection in soybean.

Root microbiota alters response to root rot in Rhododendron delavayi Franch.

Root microbiota have a significant effect on plant health. However, the role of root microbiota in the resistance of Rhododendron against root rot is not known. In this study, we employed amplicon 16S and ITS sequencing to investigate the bacterial and fungal communities associated with four distinct niches (bulk soil, rhizosphere, rhizoplane, and endosphere) of both healthy and diseased Rhododendron plants in the Baili Rhododendron nature reserve in China. The amplicon data analysis identified 182 bacterial genera and 141 fungal genera that were impacted by root rot across all niches. Specifically, the rhizoplane appeared to exert a selective gating effect, resulting in a reduction in the complexity of bacterial communities, but not fungal communities, in wild Rhododendron delavayi Franch roots. Nevertheless, the stress induced by root rot led to alterations in the root microbiota and compromised the gating function of the rhizoplane, thereby significantly increasing the complexity of the bacterial community within the plant root. In the root tissue following root rot outbreak, the relative abundance of the pathogenic species Pezicula brunnea and Diaporthe helianthi was enriched by as much as 6.13% and 1.71%, respectively. These findings provide novel insights into the contribution of enrichment of root-associated microbiota to wild plant hosts under the disease stress of root rot. The root rot-causing pathogenic fungi may interact with beneficial bacteria and induce plants to send out "cry for help" signals, which may encourage the specific assembly of microbiota. In the Rhododendron delavayi Franch root microbiota, we found 23 potentially beneficial microbes. Notably, certain beneficial bacteria, such as Sporolactobacillus and Stenotrophomonas, were found to accumulate in the rhizoplane and endosphere under root rot disease stress. Overall, our results lend support to our hypothesis that Rhododendron recruits protective microbes as a strategy to suppress root rot outbreaks. Future endeavors in isolating beneficial microbes capable of mitigating root rot have the potential to enhance plant resilience against root diseases.

HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation.

HDAC3 and HDAC8 have critical biological functions and represent highly sought-after therapeutic targets. Because histone deacetylases (HDACs) have a very conserved catalytic domain, developing isozyme-selective inhibitors remains challenging. HDAC3/8 also have deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Proteolysis-targeting chimeras (PROTACs) can selectively degrade a target enzyme, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3/8 without triggering pan-HDAC inhibitory effects. Unbiased quantitative proteomic experiments confirmed its high selectivity. HDAC3/8 degradation by YX968 does not induce histone hyperacetylation and broad transcriptomic perturbation. Thus, histone hyperacetylation may be a major factor for altering transcription. YX968 promotes apoptosis and kills cancer cells with a high potency in vitro. YX968 thus represents a new probe for dissecting the complex biological functions of HDAC3/8.