Biology subjects

Zhang, J.

Publications and source records attributed to Zhang, J..

At least 433 records · Page 24Linked to original sources

bioRxiv2025

Type one protein phosphatases (TOPPs) catalyze EIN2 dephosphorylation to regulate ethylene signaling in Arabidopsis

TOPPs (Type one protein phosphatases) widely modulate plant hormone signaling and stress responses in plants, but their roles in ethylene signal transduction remain unknown. This study reveals a reciprocal regulatory relationship between TOPPs and EIN2 (Ethylene insensitive 2)-mediated ethylene signaling. We identified that ethylene can induce TOPPs expression, and topp1/4/5 triple mutants exhibited partial ethylene insensitivity with reduced EIN3 protein levels and ERF1 (Ethylene response factor 1) expression. Mechanistically, TOPPs genetically act upstream of EIN2, physically interacting with its carboxyl-terminal domain (EIN2-C) to dephosphorylate the critical S655 residue. This site-specific dephosphorylation promotes EIN2 stability and EIN2-C nuclear accumulation, thereby activating ethylene responses. Notably, transgenic plants expressing phosphorylation-deficient EIN2S655A displayed constitutive ethylene responses and improved salt tolerance. Further investigation showed that EIN3/EIL1 (EIN3 like 1) transcriptionally activates TOPPs expression by binding to their promoter, amplifying ethylene signaling accordingly. Together, our finding establishes TOPPs play an important regulatory role in ethylene signal transduction and elucidate a dephosphorylation-switch mechanism in controlling EIN2 function, providing critical insight into the role of EIN2 post-translational modifications in plant stress adaptation.

plant biology↗

bioRxiv2025

Crosstalk between Immune Microenvironment and Hair Follicle Cells Underlies Sexual Dimorphism in Androgenetic Alopecia

Androgenetic alopecia (AGA), also known as female pattern hair loss (FPHL) in women, is the most prevalent form of hair loss. It is characterized by progressive miniaturization of hair follicles and shortening of the anagen phase. The condition is widely attributed to genetic predisposition and androgen-mediated activation of androgen receptors. Other factors, such as the immune microenvironment, could also contribute to the pathogenesis. However, the specific mechanisms involved are still poorly understood. This study aimed to investigate the potential role of skin-resident myeloid cells in interacting with hair follicle cells under androgen stimulation, and to elucidate the sex-specific differences in dihydrotestosterone (DHT)-induced hair loss. Both female and male mice received DHT treatment, and histological examination was performed to assess DHT-induced alterations in skin morphology. Single-cell RNA sequencing (scRNA-seq) was utilized to profile skin cell populations and explore underlying mechanisms. Our results demonstrated that DHT inhibited hair regrowth in both sexes, altered skin thickness, and induced hair follicle miniaturization. scRNA-seq analysis revealed enhanced interactions between myeloid and fibroblast subpopulations, with more robust crosstalk observed in female mice. An in vitro experiment demonstrated that DHT promoted apoptosis of dermal papilla cells (DPCs) in the presence of macrophages. Treatment with polypeptides Y001 and Y002 effectively promoted hair regrowth by suppressing apoptosis signaling pathways. Our findings underscore the interactions between immune cells and hair follicular cells, particularly mediated by skin-resident myeloid cells, in the sexual dimorphism of androgenetic alopecia. The polypeptides Y001 and Y002 exhibit promising therapeutic potential by targeting apoptotic pathways, offering novel avenues for AGA treatment.

cell biology↗

bioRxiv2025

Programmable Aptamer-Embedded Circular RNAs for Targeted Antigen-Presenting Cells Immunotherapy

The targeted delivery of mRNA to specific cell types in vivo remains a major unmet need in mRNA-based therapeutics. Conventional strategies rely on nanocarriers engineered with various modifications. However, these exogenous materials could cause adverse reactions, and their complex manufacturing processes often hinder clinical application. By leveraging the innate programmability of RNA sequences, we herein report a carrier-free, scalable, and programmable aptamer-embedded circular RNAs (Apt-circRNAs) design that confers targeting capability through the strategic incorporation of different aptamers at varying densities, while retaining circular RNA stability and protein production capability. Experimental results show that antigen-loaded Apt-circRNAs enable targeted delivery to antigen-presenting cells (APCs), drive endogenous antigen expression, activate antigen-specific T cells, and elicit potent immune responses that mediate clearance of both early-and late-stage tumors in mouse models. In humanized models of colorectal cancer, the combination of Apt-circRNA and PD-1 blockade produced synergistic antitumor effects and significantly reshaped the tumor microenvironment. In a first-in-human (FIH) clinical trial, Apt-circRNA vaccine encoding KRAS G12D/G12V neoantigens exhibited a favorable safety profile and induced robust immune activation, T cell mobilization, and neoantigen-specific immune responses. With this study, we have established a new paradigm in carrier-free, APC-targeted RNA vaccine design, offering a safe and effective platform for next-generation cancer immunotherapy.

bioengineering↗

bioRxiv2025

STAT3 operates as an inflammation-dependent transcriptional switch

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of immune cell function, but its role in lymphocytes remains incompletely understood. Here, we show that STAT3 has a context-dependent function in antiviral natural killer (NK) cells, either promoting or impairing adaptive NK cell responses dependent on the level of inflammation. STAT3 is recruited to distinct genomic sites under homeostatic versus inflammatory environments, where it drives different transcriptional programs. Through this re-localization, STAT3 regulates downstream transcription factors MYB and BLIMP-1 in an inflammation-dependent manner to shape NK cell differentiation under homeostasis and during infection. Thus, STAT3 acts as a transcriptional switch that integrates cytokine signals to control lymphocyte adaptation to different environments. This mechanism highlights how therapeutic interventions targeting STAT3 can result in different outcomes depending on the degree of inflammation. HIGHLIGHTS- STAT3 exerts a context-dependent role on adaptive NK cells during viral infection - STAT3 modulates IL-15 signaling by competing with STAT5 and regulating MYB - Homeostatic versus inflammatory cytokines relocate STAT3 to distinct genomic sites - Downstream transcription factors MYB and BLIMP-1 govern STAT3-dependent differentiation

immunology↗

bioRxiv2025

PRRT2 as an auxiliary regulator of Nav channel slow inactivation

During sustained activity, voltage-gated sodium (Nav) channels enter a slow-inactivated state to limit cellular hyperexcitability. Disruption of this regulatory process has been implicated in skeletal, cardiac and neurological disorders. While the kinetics of this process are well characterized, its endogenous modulators remain unclear. Here, we identify Proline-Rich Transmembrane Protein 2 (PRRT2) as a native regulator of Nav channel slow inactivation. We show that PRRT2 facilitates the entry of Nav channels into the slow-inactivated state and delays their recovery, a regulatory effect conserved from zebrafish to humans. PRRT2 forms molecular complexes with Nav channels both in vitro and in vivo. In the mouse cortex, PRRT2 deficiency impairs the slow inactivation of Nav channels in neuronal axons, leading to reduced cortical resilience in response to hyperexcitable challenges. Together, these findings establish PRRT2 as a physiological modulator of Nav channel slow inactivation and reveal a mechanism that supports cortical resilience to pathological perturbations.

neuroscience↗

bioRxiv2025

A Low-dimensional Manifold Representation of the Human Brain Aging Continuum

Brain aging involves complex structural changes that challenge traditional analytical methods and hinder personalized assessment of brain health. Integrating regional brain alterations into a unified, interpretable representation is difficult due to the high dimensionality of neuroimaging data. Here, we projected regional brain volumes from the Human Connectome Project Aging Dataset onto a low-dimensional manifold that reflects underlying neuroanatomical constraints. We then built a transparent framework on the manifold to estimate brain age and identify key regional drivers of the estimate. By analyzing local neighborhoods on the manifold, we identified distinct structural aging trajectories, including pronounced frontal atrophy occurring predominantly in males. This approach provides a biologically interpretable means of characterizing individual brain-aging patterns, reveals heterogeneous aging pathways, and supports more personalized assessments and insights into the aging process. TeaserA manifold representation can map brain aging patterns across regions and reveal distinct trajectories

bioengineering↗

bioRxiv2025

Pocket-based molecule generation with an SE(3)-equivariant language model leads to a potent and selective HPK1 inhibitor with in vivo efficacy

Deep learning shows promise in structure-based drug discovery, yet challenges persist in generating pharmacologically plausible molecules with valid 3D conformation and decent binding mode in the pocket. We introduce SE3-BiLingoMol, an SE(3)-equivariant Transformer for pocket-based 3D molecule generation, addressing two key limitations of existing language-model approaches. First, it uses Geometric Algebra Transformers for SE(3)-equivariant handling of continuous 3D coordinates. Second, a bidirectional attention mechanism mitigates conformational errors accumulated during autoregressive sampling. These innovations enable SE3-BiLingoMol to generate 2D drug-like, 3D geometrically valid molecules with superior binding modes. Validated on DUD-E dataset containing over 100 targets, the model achieved state-of-the-art performance in de novo design and optimization. We applied SE3-BiLingoMol to design potent and selective inhibitors for HPK1, a promising immunotherapy target. Through an iterative human-AI workflow, integrating AI generation with experimental validations (X-ray crystallography, bioassays), we identified Cmpd. 6. This novel tetracyclic compound demonstrates potent HPK1 inhibition, excellent cellular activity, favorable pharmacokinetics, and robust anti-tumor in vivo efficacy as monotherapy and with PD-1 blockade. Our work establishes a sophisticated generative AI framework for 3D molecule design and demonstrates its application in developing cancer immunotherapy. Highlights[bullet] SE(3)-Equivariant Language Model for Molecule Generation: We introduce a dual-channel SE(3)-equivariant language model that supports de novo molecule design and optimization, addressing key challenges in prior language model-based 3D molecule generation approaches. [bullet]Discovery of Potent HPK1 Inhibitors: Application of this model led to the discovery of highly selective HPK1 inhibitors with robust in vivo efficacy, resulting in a promising lead compound. [bullet]AI-Guided Rational Drug Development Paradigm: This work establishes a paradigm for AI-guided rational drug development, showcasing AI as a "co-pilot" that inspires drug designers with novel ideas in an "evidence-based context".

bioinformatics↗

bioRxiv2025

Uterine immune dysregulation after asynchronous transfer induced embryonic apoptosis in mice

Asynchronous embryo transfer is widely used in assisted reproduction, yet its adverse effects and mechanisms remain unclear. This study investigates implantation failure in D1.5 pseudopregnant mice to elucidate mechanisms underlying asynchronous transfer. Blastocysts were transferred into uterine horns of D1.5 (Group A), D2.5 (Group B), and D3.5 (Group C) recipients. Implantation sites were counted at D7.5, and embryos were recovered within 3 hours post-transfer for analysis. Multibarcode single-cell RNA sequencing was applied to embryos and uterine tissues. Embryo recovery rate in Group A was significantly lower than in Groups B and C (p<0.01), with an abnormal embryo rate of 68.67%. Hoechst 33342/PI double staining revealed dead-cell features in abnormal embryos. Transcriptomic analysis of embryos showed downregulated DNA damage repair and structural maintenance genes in Group A. GO and KEGG analyses highlighted enrichment in transcriptional regulation and cell cycle pathways. GSEA identified activated apoptosis pathways, with intrinsic (mitochondrial) and extrinsic (death receptor TNFR-mediated) apoptosis genes significantly upregulated (p<0.05). Uterine transcriptome analysis revealed downregulated collagen family genes (ECM maintenance) but upregulated immune-related genes (IL family, CDs, C3) in Group A. Functional enrichment confirmed ECM and immune regulation pathway involvement. Gene network analysis identified Clca1, Smpdl3a, Tmprss4, Muc4, Cfb, and Nupr1 as key regulators of D1.5 uterine immunity/inflammation. D1.5 uterine immune dysregulation induces embryonic stress and inflammation. Impaired DNA damage repair activates intrinsic apoptosis, while upregulated TNFR signaling triggers extrinsic apoptosis, collectively blocking embryonic development toward implantation competence. These findings provide mechanistic insights into optimizing embryo transfer timing and improving reproductive outcomes.

immunology↗

bioRxiv2025

Blood-derived dietary protein promotes sleep in the mosquito Aedes aegypti

Sleep is a ubiquitous, yet highly variable, behavior across species. The duration and timing of sleep are influenced by ecological demands and dietary context. In the mosquito Aedes aegypti, a blood-feeding insect with specialized nutritional requirements, the relationship between feeding and sleep remains poorly understood. Here, we investigated how blood-derived dietary protein influences sleep regulation. Using postural analysis, videography, and arousal-threshold assays, we established that immobility bouts of [≥]10 minutes reliably define sleep in Ae. aegypti. Mosquitoes lacking the circadian clock gene cycle still maintained daily sleep rhythms but exhibited reduced sleep duration and heightened overall activity. Infrared activity monitoring revealed that blood-fed females showed a marked increase in sleep beginning immediately after feeding and persisting for several days, accompanied by reduced locomotor activity. Notably, this sleep elevation lasted well beyond the cessation of previously reported host-seeking phases, raising the possibility of distinct phases of opportunistic versus targeted host pursuit. To determine the dietary basis of this effect, we tested mosquitoes fed a bovine serum albumin (BSA)-based diet. BSA feeding alone was sufficient to mimic the sleep-promoting and activity-reducing effects of blood, suggesting dietary protein is a major nutritional regulator. Moreover, RNAi-mediated knockdown of the leucokinin receptor (Lkr), which has previously been associated with fluid homeostasis and feeding behavior, resulted in enhanced sleep and reduced activity, implicating mosquito LK signaling in the modulation of postprandial sleep. Together, these findings demonstrate that blood-derived proteins drive sustained increases in sleep and reductions in locomotor activity in Ae. aegypti. This work positions Ae. aegypti as a model for dissecting nutrient-specific regulation of sleep and highlights potential adaptive functions of protein-induced quiescence, such as energy conservation and predator avoidance. More broadly, it provides insight into how specialized diets shape the neural and behavioral architecture of sleep.

neuroscience↗

bioRxiv2025

Water body size shapes body size evolution via subgenomic selection in allopolyploid fish

Allopolyploidization is a major force in species evolution, and studying allopolyploids in diverse environments provides insights into their genetic mechanisms. Here, we investigated how water body size variation influences body size in allopolyploid fish. We used a nascent allopolyploid lineage derived from goldfish (Carassius auratus) and common carp (Cyprinus carpio) and established two populations in small and large water bodies for two generations. Genomic, transcriptomic, and epigenomic analyses revealed that the larger population had higher genetic diversity in subgenome R, while the smaller population had higher diversity in subgenome C. Potential selection regions were associated with growth regulatory genes, suggesting a role for gene regulation in body size adaptation. Dynamic gene expression patterns in various tissues indicated potential mechanisms underlying muscle development and adaptation to smaller water bodies. Furthermore, selection regions were linked to changes in chromatin accessibility, with subgenome R being more susceptible to these changes during genetic divergence. Our findings demonstrate that water body size variation drives body size in allopolyploid fish through subgenomic selection, impacting genetic variation, gene regulation, and epigenetic mechanisms.

genomics↗

bioRxiv2025

PRIME: A Multi-Agent Environment for Orchestrating Dynamic Computational Workflows in Protein Engineering

Artificial intelligence (AI) is revolutionizing protein engineering, yet its practical application is often hindered by a fragmented toolchain and the specialized expertise required to orchestrate complex computational workflows. To address these challenges, we have developed PRIME, an autonomous protein engineering multi-agent system. The core innovation of PRIME is dynamic workflow synthesis: it interprets high-level engineering objectives, reasons over a curated library of more than 65 validated protein tools, and autonomously constructs custom computational pathways. Crucially, by grounding every step in verifiable tool execution, PRIME mitigates the risk of model hallucination. It also automates the complete pipeline for developing specialized AI models, from data acquisition through training. In a benchmark of 213 multi-step protein engineering tasks, PRIME exhibited superior performance, successfully completing the majority of tasks where state-of-the-art, general-purpose AI agents fail. We validated its capabilities in demanding real-world applications, including the fully autonomous training of a machine learning classifier and the de novo design of a therapeutic antibody against SARS-CoV-2. By abstracting technical complexity, PRIME empowers scientists to execute sophisticated computational experiments with unprecedented flexibility, establishing a new paradigm for autonomous scientific discovery. The PRIME agent and source code will be made publicly available.

bioinformatics↗

bioRxiv2025

Focal adhesion pathway inhibition is the central axis of macrophage phenotypic responses to monoclonal antibody therapy in aggressive lymphoma via high-throughput screening and high-content imaging

High-grade B-cell lymphoma (HGBCL) frequently arises as a refractory or relapsed state of diffuse large B-cell lymphoma (DLBCL) and is associated with poor outcomes due to multi-drug resistance and hallmark oncogenic translocations. To identify novel therapeutic strategies, we developed a dual high-throughput screening (HTS) and high-content imaging (HCI) macrophage-tumour co-culture platform that quantifies antibody-dependent and antibody-independent cellular phagocytosis (ADCP/AICP) across a 1,241-compound library. Using GFP+ HGBCL cells and mCherry+ macrophages, we validated our methodology through time-resolved phenotypic profiling, Euclidean distance-based analysis, and hit compound prioritisation. Pathway interrogation revealed focal adhesion as a central hub of macrophage phenotypic modulation, highlighting focal adhesion kinase (FAK/PTK2) as a candidate therapeutic target. Pharmacological inhibition with PF-562271 enhanced phagocytic activity, altered macrophage morphology, and synergised with anti-CD20 monoclonal antibodies in vitro and ex vivo. In vivo, Rituximab plus PF-562271 significantly reduced lymphoma burden and prolonged survival in xenograft models. Collectively, our work demonstrates that HTS/HCI-driven phenotypic profiling of tumour-associated macrophages can uncover actionable therapeutic combinations and nominates FAK inhibition as a promising strategy to potentiate antibody immunotherapy in HGBCL.

cell biology↗

bioRxiv2025

A deep reinforcement learning platform for antibiotic discovery

Antimicrobial resistance (AMR) is projected to cause up to 10 million deaths annually by 2050, underscoring the urgent need for new antibiotics. Here we present ApexAmphion, a deep-learning framework for de novo design of antibiotics that couples a 6.4-billion-parameter protein language model with reinforcement learning. The model is first fine-tuned on curated peptide data to capture antimicrobial sequence regularities, then optimised with proximal policy optimization against a composite reward that combines predictions from a learned minimum inhibitory concentration (MIC) classifier with differentiable physicochemical objectives. In vitro evaluation of 100 designed peptides showed low MIC values (nanomolar range in some cases) for all candidates (100% hit rate). Moreover, 99 our of 100 compounds exhibited broad-spectrum antimicrobial activity against at least two clinically relevant bacteria. The lead molecules killed bacteria primarily by potently targeting the cytoplasmic membrane. By unifying generation, scoring and multi-objective optimization with deep reinforcement learning in a single pipeline, our approach rapidly produces diverse, potent candidates, offering a scalable route to peptide antibiotics and a platform for iterative steering toward potency and developability within hours.

molecular biology↗

bioRxiv2025

Co-evolution of a near-infrared aptamer:dye system for live-cell super-resolution RNA imaging

Despite their advantageous properties for live-cell imaging and super-resolution microscopy, high-performance silicon rhodamine (SiR) near-infrared (NIR) probes are still rarely employed in RNA imaging via fluorescent light-up aptamers (FLAPs). Here, we developed the SiRiuS:SiR-5 system through a combined evolutionary approach: evolving the aptamer via fluorescence-activated cell sorting (FACS), along with targeted mutations, truncations, and rational design, and improvement of the dye by systematic chemical derivatization. This resulted in an aptamer:dye pair with high fluorogenicity and photostability, specifically optimized for visualization of RNAs in mammalian live cells. Our system demonstrates strong fluorescence enhancement in live-cell imaging, enabling time resolved imaging of dynamic processes such as stress-granule formation. Notably, we validate its application in STED super-resolution microscopy, establishing it as a powerful NIR imaging platform for RNA structures below the refraction limit. Its orthogonality to existing FLAPs operating in the yellow-orange spectrum further broadens its versatility for exploring complex RNA dynamics in live cells. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/677088v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@11051eeorg.highwire.dtl.DTLVardef@7309d6org.highwire.dtl.DTLVardef@8ac3e8org.highwire.dtl.DTLVardef@43eafd_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Efineptakin alfa (NT-I7) improves overall survival and induces tertiary lymphoid structures in murine lung tumors

Tertiary lymphoid structures (TLSs) are emerging as good predictive biomarkers of response to cancer immunotherapy. However, therapeutic strategies to induce these structures are currently limited. We evaluated the therapeutic benefit of efineptakin alfa (NT-I7), a long-acting form of IL-7, and its ability to induce TLSs in a murine lung tumor model. NT-I7 improved overall survival in tumor-bearing mice. It also increased the abundance of T, B, dendritic cells, and stem-like CD8 T cells and promoted the formation of immune aggregates in the tumor microenvironment (TME). Stem-like CD8 T cells were preferentially located in the immune aggregates. Spatial transcriptomic analyses of the TME further demonstrated that the immune aggregates induced by NT-I7 included TLSs with enrichment of Cd274 (PD-L1) transcripts and genes involved in antigen processing and presentation. Upregulation of Cd274 in the TLSs may provide opportunities for synergy between NT-I7 and PD-1-targeted immunotherapy. STATEMENT OF SIGNIFICANCEThis study demonstrates the ability of efineptakin alfa (NT-I7) to potentially augment the clinical efficacy of cancer immunotherapy by inducing tertiary lymphoid structures in the tumor microenvironment.

immunology↗

bioRxiv2025

Single-nucleus transcriptomics reveal disrupted pathways in the prefrontal cortex of Scn2a-deficient mice

Truncating variants in SCN2A, which encodes the NaV1.2 sodium channel critical for action potential initiation and propagation, are associated with autism spectrum disorder (ASD) and epilepsy. To investigate SCN2A deficiency-related phenotypes, we developed a preclinical mouse model with under 50% NaV1.2 expression, exhibiting neuronal hyperexcitability and social deficits. However, the neuronal populations and molecular alterations underlying these phenotypes at single-cell resolution have not been investigated. In this study, we conducted single-nucleus RNA sequencing (snRNA-seq) of wild-type (WT), homozygous Scn2a-deficient (HOM) mice, and HOM mice with Scn2a restoration (HOM-FlpO) to examine the effects of Scn2a level on gene expression in the medial prefrontal cortex (mPFC), a critical brain region related to ASD development. Differential expression analysis in GABAergic and glutamatergic neurons between genotypes revealed gene expression enriched in neurotransmitter activity regulation and synapse organization. Lastly, snRNA-seq results in HOM-FlpO identified genes that were rescued after Scn2a restoration. These results reveal that reduced Scn2a expression disrupts RNA transcriptomes in multiple neuronal subtypes, providing insight into cell type-specific mechanisms underlying SCN2A-related disorders.

neuroscience↗

bioRxiv2025

Distinct neural moderators of resilience and vulnerability confer heterogeneous outcomes following early-life adversity

Early-life adversity (ELA) increases risk for psychiatric disorders, but outcomes are highly variable. Using multimodal neuroimaging and computational moderation in large adolescent cohorts, we systematically identify brain features that buffer or amplify effects of three ELA subtypes--familial interpersonal, non-familial interpersonal, and non-interpersonal adversity--on transdiagnostic psychopathology. Multimodal neural moderators were subtype- and pathology dimension-specific, revealing distinct neurobiological mechanisms moderating heterogeneous outcomes. Protective features clustered in limbic, sensory integration, and regulatory circuits (amygdala, parietal cortex, anterior cingulate), while vulnerability features concentrated in frontotemporal circuits. Individual features and a new Relative Resilience Index (RRI)--reflecting the individual balance between protective and vulnerability features across the whole-brain--prospectively predicted psychopathological progression over two years, linking brain signatures to future mental health trajectories. Findings establish the brain as dynamic moderator of distinct adversity effects and introduce a system-level marker for risk stratification, advancing mechanistic precision in youth mental health and guiding early intervention.

neuroscience↗

bioRxiv2025

Discovery of A Small Molecule non-IMiD Degrader of ZBTB7A for the Treatment of β-hemoglobinopathies

Sickle cell disease and {beta}-thalassemia, two major {beta}-hemoglobinopathies, pose significant clinical challenges globally. Current treatments often face limitations in efficacy and tolerability. The transcription factor ZBTB7A has emerged as a promising therapeutic target for reactivating fetal hemoglobin expression. Here, we report the discovery and characterization of SH6, a small molecule non-IMiD degrader of ZBTB7A. SH6 induces fetal hemoglobin in erythroid cell lines in a CRBN and ZBTB7A-dependent manner, and it is capable of inducing fetal hemoglobin expression in healthy donor, SCD and {beta}-thalassemia patient CD34+ cell derived erythroid cells. The efficacy of SH6 is confirmed in a xenotransplantation humanized mouse model. SH6 outperforms currently available therapeutic agents in vitro, and shows synergy with hypomethylating agents. SH6 exhibits a favorable in vivo toxicity profile. Our findings establish SH6 as a promising therapeutic lead candidate for further optimization towards clinical development for treatment of sickle cell disease and {beta}-thalassemia.

cell biology↗