Biology subjects

He, H.

Publications and source records attributed to He, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Harnessing Tumor-Specific Transcript Diversity Uncovers a Shared Neoantigen Reservoir for Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is refractory to immunotherapy due to its immunologically cold microenvironment and the scarcity of mutation-derived neoantigens. Here, we introduce NeoAPP, a computational tool designed to systematically decode neoantigens arising from tumor-specific transcripts (TSTs) generated by transcriptional dysregulation. Multi-cohort transcriptomic profiling of 413 PDAC samples using NeoAPP reveal a median of 351 neoantigens per sample derived from 56 neoantigen-encoding TSTs (neoTSTs), surpassing mutation-derived counterparts in both abundance and patient coverage. Mechanistic analyses show that non-canonical splicing junction and transposable element activation drive neoantigen generation, while FOXA2-regulated promoter usage constitutes a potential major source of neoTSTs. Tumor-derived neoTSTs are also detected in extracellular vesicles and cancer-associated fibroblasts, implicating stromal crosstalk in immune modulation. Vaccination with neoTSTs induce CD8+ T cell responses in HLA-A*02:01/A*11:01 transgenic mice and suppressed tumor growth in syngeneic PDAC models. Collectively, this work establishes TST-derived neoantigens as a dominant and therapeutically actionable antigen reservoir in PDAC, advancing a transcriptome-guided framework for neoantigen discovery with potential to overcome immune resistance in low-mutation cancers. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/705024v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@82ff31org.highwire.dtl.DTLVardef@401342org.highwire.dtl.DTLVardef@b0771corg.highwire.dtl.DTLVardef@15c03ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Large-scale quantum computing framework enhances drug discovery in multiple stages

Coherent Ising machines (CIMs) excel at solving large-scale combinational optimization problems (COPs), but their insufficient long-term stability has hindered their applications in compute-intensive tasks like computer-aided drug discovery (CADD). By improving fiber vibration isolation and temperature control system, we have implemented a 2000-node CIM named QBoson-CPQC-3Gen achieving stable solutions over one hour on large-scale COPs. Graph-based encoding schemes were further introduced to realize a CIM-based CADD workflow including allosteric site detection, protein-peptide docking and intermolecular similarity calculation. CIM-based methods demonstrated superior speed and accuracy than heuristic algorithms. Especially, QBoson-CPQC-3Gen identified 2 novel druggable sites and bioactive compounds for 6 targets, which were further validated in vitro, in-cell and by crystal structures. Our contributions established a quantum-computing framework for multi-stage drug discovery, representing a significant advancement in both quantum computing applications and pharmaceutical research.

bioinformatics↗

bioRxiv2026

Noncanonical loops regulated by EMF1 and cohesin-associated factors shape the distinct 3D genome architecture in plants

In mammals, cohesin-mediated chromatin loop extrusion is blocked at boundaries, where CTCF, WAPL, and PDS5s co-bind and regulate cohesin, establishing an impermeable barrier with no exceptions. In contrast, our study revealed that in Arabidopsis, some noncanonical contacts have emerged between the boundary flanking regions, which suggest that cohesin is not absolutely blocked but enables sliding beyond boundaries. We identified these interactions as noncanonical loops and clarified their regulatory proteins. Firstly, the plant-specific boundary binding protein EMF1 is essential for noncanonical loops formation. Surprisingly, although both Arabidopsis WAPLs and PDS5s inhibit loop extension as mammals, PDS5s do not co-bind and cooperate with WAPLs at boundaries. Instead, PDS5s bind to boundary-flanking regions enriched with H3K4me1 through their Tudor domains, restricting further extension of noncanonical loops. Consequently, pds5a/b/c mutants lose noncanonical loops, resulting in emergence of larger canonical loops but anchored on boundaries and co-upregulation of anchored gene pairs. Collectively, our findings reveal that the plant-specific noncanonical loop, regulated by plant-specific EMF1 and PDS5 proteins, is the fundamental structure of the distinctive chromatin organization of plants, which provides novel mechanistic insights into eukaryotic chromatin architecture regulation.

plant biology↗

bioRxiv2026

Geometric structure of features underlies human VTC object recognition.

The ventral temporal cortex (VTC) plays a crucial role in human object recognition. Within VTC neural space, object-specific domains align with domain-general features, e.g. face- and scene-domain align with the feature distribution of animacy, generating a hierarchical knowledge structure for categorization. However, the neural process of integrating information from VTC to distinguish different objects remains unclear. Here, we employed a combination of ANN modeling, functional MRI, and MEG to investigate how VTC features affect object manifold separability. The representational geometry analysis shows that domain-general features in VTC form a unique structure, different from ANN, to assist object classification. Moreover, VTC dynamically adjusts the geometrical relationship of these features during object recognition, influencing the geometrical properties of object manifolds and, consequently, their separability. These findings advance our understanding of the neural computation involved in VTC object recognition, revealing how downstream neurons can flexibly access category information in diverse recognition tasks.

neuroscience↗

bioRxiv2026

Optimizing broadly neutralizing antibodies via all-atom interaction modeling and pre-trained language models

Antibody optimization is a fundamental challenge, and the identification of antibody-antigen interactions is crucial in the optimization process. However, current methods cannot accurately predict antibody-antigen interactions, providing limited functional guidance to improve the time-consuming and costly traditional optimization techniques. Here, we present InterAb and InterAb-Opt, a unified computational framework that integrates all-atom modeling with antibody language models to predict antibody-antigen interactions and enable antibody optimization. Leveraging the proposed all-atom modeling approach, AtomInter, and pre-trained antibody language models, InterAb outperforms existing methods in predicting antibody specificity and antibody-antigen binding affinity. InterAb successfully identified influenza A virus-binding antibodies from an antibody library and accurately detected high-affinity antibodies in the AIntibody competition. Empowered by the robust functional insights from InterAb, InterAb-Opt was developed to optimize broadly neutralizing antibodies. For R1-32 antibody, biolayer interferometry results reveal that 85%, 80%, 90%, and 67.5% of the 40 InterAb-Opt-optimized antibodies exhibit enhanced binding affinities to wild-type SARS-CoV-2, Lambda, BQ.1.1, and EG.5.1, respectively, with a maximum improvement of up to 96-fold. For the newly emerging BA.2.86 and KP.3, 55% and 52.5% of the optimized antibodies notably transition from non-binding to binding. Neutralization assays demonstrated that the optimized antibodies exhibited enhanced neutralization activity across multiple targets, highlighting the capability of InterAb-Opt in engineering broadly neutralizing antibodies. This technology enables precise analysis of antibody-antigen interactions and optimization of broadly neutralizing antibodies, holding promise for addressing challenges in immune evasion and vaccine design.

bioinformatics↗

bioRxiv2026

Combining evolution and machine learning-guided pathway optimization to engineer a novel methylsuccinate module for synthetic C1 metabolism in vivo

De novo metabolic pathways open possibilities for sustainable biotransformations in microbes. However, the in vivo-implementation of such new-to-nature pathways is highly challenging and heavily relies on adaptive laboratory evolution (ALE) of the hosts native metabolic network. Here, we assess how much this need for host-centric ALE can be overcome and/or complemented through the informed design of the newly introduced pathway. Exemplifying for a synthetic CO2-fixation module via methyl-succinate, we established methylsuccinate-dependent growth of Escherichia coli over six months by ALE of E. colis native metabolism. In parallel, we developed a machine-learning guided workflow (MEVIS) for the automated engineering of the synthetic pathway, resulting in methylsuccinate-dependent growth within three weeks. Critically, performing MEVIS in the background of the ALE-evolved strain is necessary to further approach wild-type like growth, demonstrating how ALE in combination with machine-learning-guided lab automation holds great potential to accelerate and improve design-build-test-learn cycles in contemporary metabolic engineering.

bioengineering↗

bioRxiv2026

Reliability and validity of multi-band multi-echo fMRI

Precision mapping of individual differences in human brain spontaneous activity is critical for characterizing brain function and guiding clinical translation. Multi-echo resting-state functional MRI (ME-rfMRI) has the potential to provide more reliable mapping of inter-individual differences in intrinsic brain function than conventional single-echo rfMRI (SE-rfMRI). However, the psychometric benefits of ME-rfMRI for mapping individual differences in spontaneous brain activity (SBA) have not been systematically investigated, which is fundamental for understanding the human brain in health and disease. To quantify the psychometric performance of ME-rfMRI in precisely mapping inter-individual variations in SBA, we employed a psychometric design. We scanned 27 healthy adults with both ME-rfMRI and SE-rfMRI to assess short-term (minutes) test-retest reliability, as well as validity across eyes-open (EO) and eyes-closed (EC) resting states. Our results demonstrate that ME-rfMRI improves reliability relative to SE-rfMRI by 10.8% for amplitude of low-frequency fluctuation (ALFF), 4.4% for regional homogeneity (ReHo), and 8.0% for voxel-mirrored homotopic connectivity (VMHC) in cortical regions, and by 12.5% for ALFF, 8.3% for ReHo, and 4.0% for VMHC in subcortical regions. This enhancement is achieved by increasing inter-individual variability while reducing intra-individual variability. Notably, ME-rfMRI accentuates inter-individual variability in the unimodal cortex and clearly delineates two parallel systems with distinct variability patterns within the motor cortex. Concurrently, ME-rfMRI increases effect sizes (4%-8%) for detecting individual differences between EO and EC resting states. Interestingly, ME-rfMRI reveals differential effects of eye closure on two intertwined systems in the primary motor and sensory cortices, extending previous findings. Computational simulations indicate that, compared to SE-rfMRI, ME-rfMRI facilitates experimental designs with reduced costs (i.e., 4%-11% smaller sample sizes) for precise mapping of individual differences. These findings establish, for the first time, the psychometric performance of ME-rfMRI measurements, supporting its potential utility in personalized neuroscience applications, including neurodevelopment and brain disorders.

neuroscience↗

bioRxiv2026

Legionella and Mycobacterium populations exhibit geographic structuring across and within drinking water systems

Opportunistic pathogens (OPs) within the Legionella and Mycobacterium can persist and sometimes proliferate in drinking water systems and pose a risk to public health. Most prior research has focused on isolated system components of the drinking water treatment and distribution system and has rarely examined spatiotemporal dynamics across the entire source water, treatment process, and distribution system continuum. This study addresses this critical knowledge gap by quantitative profiling of microbial communities with full length 16S rRNA gene sequencing and flow cytometry, and associated water chemistry parameters, including disinfection byproducts (DBPs), across five full-scale utilities. These utilities reflect varying source water types, geographic locations, treatment regimes, and climate zones. Microbial communities, including Legionella and Mycobacterium populations, in distribution system were shaped by source water type and exhibited significant community divergence across utilities. Within the same genus, strain-level analyses revealed highly distinct Legionella and Mycobacterium sequence variants unique to each utility. Interestingly, a substantial proportion of Legionella and Mycobacterium amplicon sequence variants were both utility specific and often specific to locations within the distribution system, indicating strong geographic structuring both across and within drinking water systems. Understanding the mechanistic underpinnings of this geographic structuring is critical to develop robust strategies for managing and monitoring Legionella and Mycobacterium populations in drinking water systems.

microbiology↗

bioRxiv2026

Cellular basis of accelerated whole-tooth regeneration

Teeth are ectodermal organs that have, throughout their long evolutionary history, retained the capacity for full regeneration and replacement, even in adult stages. Yet, because most mammals (e.g., humans, mice) lack lifelong dental replacement, we do not fully understand its tempo and mode, and we do not have a clear picture of the cell populations and signals that contribute to the process. Here, we used cichlid fishes from Lake Malawi, species that differ in tooth formula (tooth shape and number) but share one-for-one tooth replacement, to (i) explore the tempo of dental replacement after plucking and then (ii) identify the cell populations, gene expression signatures, and interactions between cell populations that change in this plucking paradigm. We observed that cichlid species with divergent dentitions accelerated tooth replacement >3x on the plucked half of the jaw. Then, we used single-nucleus RNA-seq to profile cellular and molecular changes across the first week of post-plucking tooth replacement. This approach allowed us to infer cellular trajectories in dental epithelium and mesenchyme that underlie tooth regeneration. We identifed distinct gene expression profiles and cellular interactions across four time points of accelerated tooth replacement, with divergent involvement of epithelial, mesenchymal and immune cell types. Diferential signaling of Collagen, BMP, MMP, Semaphorin and Slit-Robo pathways was evident after plucking and highlights temporally-sequenced roles of immune response, odontogenesis, vascularization and nerve pathfinding as teeth are constructed anew. Overall, this study provides insight into the trajectory of cellular interactions accompanying whole-tooth replacement and offers a comparative foundation for understanding dental regeneration in vertebrates.

developmental biology↗

bioRxiv2026

Ultrashort optical-pin excitation for scattering brain imaging

Imaging neural structures deep in brain tissue is central to understanding brain function, yet remains fundamentally limited by strong optical scattering and the requirement for accurate three-dimensional (3D) optical sectioning. Laser-scanning microscopy is a promising technique for brain imaging; however, maintaining excitation focus integrity in scattering media while preserving axial confinement poses a persistent photonic challenge. Here we introduce the optical pin, an ultrashort excitation regime engineered at the angular-spectrum level to address this limitation. By broadening the transverse angular bandwidth of a Bessel-type field while preserving its conical momentum-space architecture, the optical pin introduces a controlled longitudinal wave-vector spread that compresses the axial interference length to the micrometer scale, restoring Gaussian-like sectioning without sacrificing multi-angle interference. This excitation design yields substantially enhanced imaging performance, including [~]1.5-fold contrast improvement and [~]2.6-fold increased robustness to scattering. We validate the approach across transparent, scattering, and biological specimens, including bead phantoms, C. elegans, and mouse brain tissue. As a system-level excitation strategy, the optical pin is readily compatible with existing laser-scanning microscopy platforms and is particularly suited for scattering-limited brain imaging.

neuroscience↗

bioRxiv2025

A shared genetic regulator of metabolism and addiction-related behavior in mice and humans

Substance use disorders and other mental health conditions often co-occur with metabolic disorders, suggesting shared biological underpinnings1. These heightened behavioral and physiological responses may have evolved to promote survival during resource scarcity but can become maladaptive in modern environments2. The genetic mechanisms linking these traits have remained elusive. Here, we show that a variable gene enhancer in mice jointly regulates genes encoding an epigenetic factor (Eed) and a mitochondrial enzyme (Me3) thereby influencing propensity to addiction-related behaviors and mitochondrial function. We further identify variation in a corresponding enhancer in humans regulating EED and ME3 associated with substance use, psychiatric and metabolic disorders. These findings reveal a convergent genetic regulatory network linking mitochondrial biology to behavioral and metabolic risk, offering insight into how genetic variation in beneficial regulatory pathways can predispose individuals to substance use disorders and related conditions.

genetics↗

bioRxiv2025

Amyloid-beta relates to default and attention network connectivity during working memory retrieval

As one of the earliest pathological events in Alzheimers disease, amyloid-beta accumulation has been linked to alterations in large-scale brain networks, especially the default mode network. While most prior work has focused on resting-state functional connectivity or task-evoked activation, how amyloid-beta relates to task-modulated connectivity that directly supports behavior is less explored. Here, we examined the relationship between amyloid-beta burden and task-modulated connectivity during a Letter Sternberg verbal working-memory task in eighty-four cognitively normal older adults from an ongoing longitudinal cohort (age 56-71 years; 41 female). To further understand these connectivity alterations, we tested whether these connections were associated with task performance or with cognitive reserve factors. We found that higher amyloid-beta burden was associated with reduced connectivity specifically during the probe phase of working-memory retrieval. At the regional scale, lower node strength in posterior-medial regions of the default mode network was related to worse task performance and mediated the amyloid-behavior relationship. At the network scale, altered coupling between the default mode and dorsal attention networks was related to task performance but did not mediate the amyloid-behavior relationship. Moreover, physical activity was associated with network-level coupling but not with regional node strength. These findings suggest that amyloid-beta burden disrupts retrieval-related working-memory systems, particularly regions of the default mode network that are vulnerable to amyloid-beta, while coupling between the default mode and dorsal attention networks indexes resilience. Collectively, task-modulated connectivity provides insight into pathways through which early Alzheimers disease pathology influences working-memory performance and resilience and may inform targeted lifestyle or neuromodulation interventions for older adults.

neuroscience↗

bioRxiv2025

Gasdermin E couples mitochondrial damage to pyroptotic neurodegeneration in Parkinson disease

Parkinsons disease (PD) features progressive loss of nigrostriatal dopamine neurons, but how mitochondrial damage engages programmed cell death pathways remains unresolved. Here, we identify gasdermin E (GSDME), the caspase-3-activated executor of pyroptosis, as a critical mediator of neurodegeneration in toxin-based PD models. In primary neurons and SH-SY5Y cells, the mitochondrial complex I inhibitor MPTP/MPP triggered caspase-3 activation, GSDME cleavage, and lytic membrane rupture. Genetic silencing of Gsdme or its transcriptional regulator SP1 reduced neuronal death. In vivo, Gsdme deficiency preserved substantia nigra pars compacta dopaminergic neurons, improved motor performance, and mitigated anxiety- and depression-like behaviors after MPTP administration. Loss of Gsdme also dampened microglial and astrocytic activation and lowered proinflammatory cytokines in striatum and substantia nigra. Mechanistically, cleaved GSDME localized to mitochondria, disrupted membrane potential, increased reactive oxygen species, and precipitated organelle injury, thereby coupling mitochondrial dysfunction to pyroptotic cell death. These findings identify GSDME-mediated pyroptosis as a mechanistic link between mitochondrial toxicity and neuroinflammation in PD and nominate GSDME as a therapeutic entry point to slow disease progression. SignificanceHow mitochondrial injury kills dopamine neurons in Parkinsons disease is a central unresolved question. We show that the pyroptosis executor GSDME is required for neurodegeneration and neuroinflammation in MPTP models, mechanistically linking caspase-3 activation and mitochondrial damage to lytic cell death. Targeting GSDME may provide a strategy to protect vulnerable neurons in PD. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/694264v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@15364e7org.highwire.dtl.DTLVardef@57b65org.highwire.dtl.DTLVardef@1e85108org.highwire.dtl.DTLVardef@1200d34_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsGSDME drives PD-linked neuronal loss. Silencing GSDME (or its transcriptional factor Sp1) ameliorates MPTP-triggered neuronal cell death. Genetic ablation of Gsdme is protective in the MPTP-induced PD mouse model. Gsdme-/-mice retain nigrostriatal DA neurons, show improved motor and affective behaviors, and exhibit reduced microglial and astrocytic activation and cytokines release upon MPTP treatment. Cleaved GSDME accumulates on mitochondria, collapses {Delta}{Psi}m, raises ROS, and links mitochondrial toxicity to pyroptosis, thus positioning GSDME as a tractable target to slow PD progression.

neuroscience↗

bioRxiv2025

scProtoTransformer: Scalable Reference Mapping Across Molecules, Cells and Donors

The rapid accumulation of single-cell data has made it possible to comprehensively characterize biological systems at molecular, cellular, and donor levels. However, scalable reference mapping across different resolutions remains a major challenge in current research. Here, we propose scProtoTransformer, a prototype-based Transformer architecture designed to achieve scalable reference mapping across molecular, cell, and donor levels. scProtoTransformer introduces a knowledge-guided prototype tokenizer that projects gene expression into biologically interpretable pathway prototypes, effectively reducing numerical batch effects while preserving biological semantic patterns. Furthermore, by leveraging knowledge distilled from the foundation model and a dynamic supervised fine-tuning strategy, scProtoTransformer achieves robust biological representations with reduced pre-training requirements. Benchmark experiments across molecular, cell, and donor-level reference mapping demonstrate that scProtoTransformer delivers competitive or even superior performance compared with state-of-the-art approaches, while providing interpretability through biologically prototypes. Together, these results establish scProtoTransformer as a unified framework for scalable reference mapping, laying the foundation for systematic understanding from genes to individuals.

bioinformatics↗

bioRxiv2025

Physical proximity, social familiarity, and acoustic environment modulate heart rate synchrony in real-world social interactions

Human social behaviour unfolds in complex real-world environments influenced by social and environmental factors, yet reliable markers of social engagement and connection remain elusive. Interpersonal physiological synchrony (IPS) has been proposed as one such marker, but its occurrence in everyday settings is not well established. To investigate the social and environmental factors that influence IPS, we continuously measured heart rate, GPS, and the acoustic environment from 72 participants across three multi-day trips to New York City, capturing naturalistic social behaviour. Across all three trips, heart rates reliably synchronized when participants were in close physical proximity, indicating that shared environmental context was sufficient to elicit IPS. IPS was stronger among socially familiar peers, and context dependent, emerging during close-proximity interactions and joint attention to shared stimuli, but not dispersed interactions. IPS was also modulated by acoustic context, with low-to-moderate sound pressure levels and moderate-to-high signal-to-noise ratios enhancing synchrony, while excessive environmental noise reduced it to levels comparable to non-interactive settings, which may reflect lower levels of joint engagement in noisier environments. These findings demonstrate that IPS emerges in naturalistic social settings and is modulated by physical proximity, social familiarity, social context, and the acoustic environment, establishing IPS as a reliable marker of real-world social engagement.

physiology↗

bioRxiv2025

Inhibiting Glycan Degradation Prevents HIV-Induced Inflammaging and Cognitive Impairment

Cognitive impairment is a frequent outcome of chronic viral infections linked to premature aging, including HIV. The mechanisms underlying this decline remain poorly understood. Here, we identify pro-inflammatory glycan degradation, characterized by loss of sialic acid and galactose, alterations that are hallmarks of premature aging, as key contributors to HIV-associated cognitive impairment (HIV-CI). In two independent cohorts of people living with HIV, these degradative changes were enriched in individuals with cognitive impairment, particularly females, and correlated with worse cognitive performance. In both a humanized mouse model of HIV and Eco-HIV, a complementary model that allows behavioral testing, pharmacological inhibition of glycan degradation with sialidase inhibitors prevented virally induced inflammation, immune activation, accelerated aging, and memory deficits. These findings implicate glycan degradation as a contributor to inflammation and cognitive impairment in HIV and highlight glycan-preserving therapies as a promising strategy to mitigate inflammation, premature aging, and cognitive decline during viral infections.

microbiology↗

bioRxiv2025

Lipid peroxidation intrinsically induces mitochondrial iron overload via Bach1-HO-1 signaling to promote cardiac ferroptosis

BackgroundLipid peroxidation and iron accumulation are hallmarks of ferroptosis, a form of cell death characterized by iron-dependent oxidative damage to cellular membranes. However, the molecular link between lipid peroxidation and iron overload in the execution of ferroptosis remains elusive. Moreover, the pathophysiological implications of the interaction between lipid peroxidation and iron overload in cardiac homeostasis and remodeling are also unknown. MethodsWe assessed the role of lipid peroxidation in mediating cardiac iron overload and ferroptosis using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which lipid peroxidation regulates iron homeostasis and ferroptosis signaling in cardiomyocytes. ResultsCardiomyocyte-specific ablation of Gpx4 (glutathione peroxidase 4), a key suppressor of lipid peroxidation, promoted iron overload and ferroptosis in the heart, leading to dilated cardiomyopathy. Mice with heterozygous Gpx4 knockout were also predisposed to adverse cardiac remodeling and dysfunction following pressure overload. Mechanistically, elevated lipid peroxidation due to GPX4 inactivation intrinsically induced iron overload by promoting the nuclear export of Bach1 and subsequent induction of heme oxygenase-1 (HO-1). Genetic and pharmacologic inhibition of HO-1 markedly attenuated iron overload and ferroptosis in cardiomyocytes and rescued dilated cardiomyopathy associated with Gpx4 deficiency. Moreover, we identified HO-1 mitochondrial translocation as a key mechanism driving mitochondrial iron overload and ferroptosis. Targeted inhibition of mitochondrial iron overload or lipid peroxidation abrogated cardiac ferroptosis and pathological remodeling induced by Gpx4 deficiency. ConclusionsThese findings identified a mechanistic link between lipid peroxidation and iron overload via the Bach1-HO-1 signaling pathway, revealing new regulators and molecular targets for cardiac ferroptosis.

cell biology↗

bioRxiv2025

Pharmacological Induction of Irreversible Senescence in Drug-Tolerant Persister Cells Prevents Tumor Relapse

Despite substantial advances in targeted therapies, most patients with advanced cancers ultimately relapse. This relapse is frequently seeded by drug-tolerant persister cells (DTPs), which persist as minimal residual disease (MRD) by adopting a reversible quiescent state and later reacquire proliferative capacity under ongoing treatment. To address this, we sought to convert quiescent DTPs into an irreversible, non-proliferative state by pharmacologically inducing senescence. Through large-scale chemical screening and combination optimization, we identified SAHA plus tilorone dihydrochloride (SIC) as a regimen that robustly induces senescence in melanoma DTPs and abolishes their proliferative potential in vitro. Mechanistically, SAHA relieves HDAC1-mediated repression of HMGA2, a key senescence driver, while tilorone synergistically inhibits autophagy to promote a fully senescent state. In a melanoma xenograft mouse model receiving MAPK-targeted therapy, SIC treatment significantly suppressed MRD progression. Importantly, SIC also induced robust senescence across diverse DTP models irrespective of tumor origin, mutational background, or prior treatment. Collectively, these findings provide proof-of-concept that converting DTPs from reversible quiescence to permanent senescence represents an effective strategy to prevent relapse under targeted therapy and position SIC as a broadly applicable pharmacological approach for durable control of residual disease in advanced cancers.

cancer biology↗