Extracellular vesicles (EV) serve as critical mediators in physiological and pathological processes, holding great promise for cancer diagnosis, real-time monitoring, and prognostic applications. However, their small size and low density present considerable challenges in achieving efficient, specific, and mild isolation, which currently hinders widespread clinical translation. Here, we report a proximity-induced pH-responsive DNA switch (PPS) that enables reversible EV capture via Hoogsteen triplex formation. Specifically, dual-aptamer probes targeting EpCAM and CD63 on EV exploit membrane fluidity to form proximity-induced duplex helix, which assemble into Hoogsteen triplex helix with magnetic bead-conjugated strands at mildly acidic conditions (pH6.5) for EV capture. Crucially, simply adjusting the pH to neutral (pH7.4) triggers triplex dissociation, releasing intact EV without using chemical denaturants and preserving vesicle integrity for high-purity isolation. Under optimized conditions, this method achieves 79.4% and 72.6% EV purification efficiency in PBS and complex biological matrices, respectively, within 1 h. Furthermore, its modular aptamer design enables rapid adaptation to diverse EV subpopulations through simple probe substitution, without modifying the core framework, thereby reducing cost and complexity for broad applications. Meanwhile, due to the gentle capture-release process, the structural integrity and bioactivity of EV are well preserved, as demonstrated by wound-healing and cellular uptake assays. These advantageous features─rapid processing, high specificity, mild operation, and preservation of EV activity─indicate that the PPS strategy is a robust, nondestructive method for EV isolation. It thus holds significant potential for further application in diverse EV-related research fields such as disease diagnosis and drug delivery.
Programmable technologies that sense nucleic acid signatures in living cells and trigger cellular functions hold promise for biotechnology and medicine. Here, we develop SONAR (Sensing Of Nucleic acids using ASOs and Reverse-transcriptases), a platform that detects target DNA and RNA sequences and triggers controlled gene expression in human cells. SONAR operates through circularizable single-stranded DNA (ssDNA) sensors that, upon hybridization with complementary DNA or reverse-transcribed RNA, undergo target-dependent ligation via cellular ligases, subsequently driving expression of genetic payloads. For RNA sensing, we employ antisense oligonucleotides (ASOs) to prime targeted reverse transcription, generating complementary DNA that promotes ssDNA circularization. We demonstrate SONAR's ability to detect ssDNA, exogenous and endogenous RNA, couple sensing to programmable expression of diverse protein payloads, including reporters, recombinases, and genome editors, and enable enrichment and clonal recovery of target-positive cells from mixed populations. This platform establishes a versatile framework for targeted nucleic acid detection and inducible gene expression, with broad potential applications in diagnostics, therapeutics, and synthetic biology.
Polymer gels are fundamentally constrained by an inherent trade-off between mechanical stiffness and dynamicity, impeding the synergistic integration of high strength with adaptive functionalities such as self-healing, recyclability, and reconfigurability. Here, we present a strategy to resolve this long-standing challenge by engineering switchable hydrogen-bond clustering (HC) within a deep eutectic solvent-based adhesive gel. Precise modulation of water content triggers the reversible transition between a rigid state (elastic modulus ∼45 MPa) and a highly dynamic state (modulus reduction by 105-fold). This on-demand switching capability facilitates direct 3D printing, efficient recycling assisted by trace water, and autonomous self-healing (∼83% recovery efficiency). Crucially, the gel retains both high stiffness and robust interfacial adhesion after turning on the HC. The HC switchable strategy establishes a versatile design principle for fabricating strong, yet dynamically reconfigurable polymeric networks, with promising implications for advanced wearables, soft robotics, and adaptive adhesive technologies.
Cancer and cardiovascular diseases represent leading chronic threats to human health, with pharmacotherapy serving as the primary intervention for both. Plant-derived bioactive compounds have emerged as vital sources of antineoplastic agents. Veratramine (VEM), a naturally occurring plant steroidal alkaloid, is widely used in medicine and agriculture. Assessing the toxicity of natural compounds to living organisms is crucial, given the pivotal role of the cardiovascular system in maintaining physiological homeostasis. Nevertheless, the potential toxicity of natural compounds to this vital system remains poorly understood. Herein, we used zebrafish as a model system to evaluate the effects of VEM on cardiac development. Our results demonstrated that VEM impairs zebrafish larval development, with cardiovascular toxicity manifested as yolk sac edema, pericardial edema, increased heart size, reduced atrial-ventricular overlap, increased distance between the sinus venosus and bulbus arteriosus, abnormal cardiac looping, cardiac ejection disorders, and decreased heart rate. Specifically, VEM dysregulates the expression of genes involved in cardiac development, induces oxidative stress in the cardiac region of zebrafish larvae, and triggers cardiomyocyte apoptosis and abnormal proliferation, ultimately leading to cardiac injury. Furthermore, our study is the first to show that VEM exposure activates the Wnt/β-catenin pathway and treatment with a Wnt signaling inhibitor rescues both VEM-induced cardiac developmental defects and oxidative stress. Taken together, our findings indicate that VEM induces cardiac developmental defects in zebrafish larvae by inducing oxidative stress and activating the Wnt/β-catenin pathway.
Anaphylaxis during pregnancy is a rare but potentially life-threatening condition for both mother and fetus, requiring rapid recognition and immediate treatment. Although the fundamental mechanisms of anaphylaxis in pregnancy are similar to those in nonpregnant women, physiological adaptations of pregnancy, peripartum exposures, and fetal considerations substantially complicate diagnosis, management, and prevention, contributing to variability in care and avoidable adverse outcomes. In this multidisciplinary review, experts in allergy-immunology, obstetrics, anesthesiology, and epidemiology synthesize current evidence on the epidemiology, triggers, pathophysiology, diagnostic challenges, management, outcomes, and prevention of anaphylaxis throughout pregnancy, labor, and delivery. We highlight how gestational cardiovascular and respiratory changes may obscure classic diagnostic features, emphasize the safety and critical importance of prompt intramuscular epinephrine use as first-line therapy, and review maternal and fetal outcomes associated with timely versus delayed intervention. Strategies for risk stratification, allergology workup, prevention of recurrence, and implementation of coordinated care pathways are discussed. This review underscores the need for increased awareness, structured interdisciplinary collaboration, and integration of prevention-focused strategies across obstetric and allergy care. By providing a practical, evidence-based framework, it aims to support health professionals in optimizing diagnosis, management, and maternal-fetal safety when anaphylaxis occurs during pregnancy.
Osmotic stress-induced Ca2⁺ accumulation promotes the formation of specific RFP-ATG8i labeled autophagosome near the hypocotyl-root transition zone, suggesting ATG8i-dependent autophagy or reticulophagy, as a mechanism to alleviate osmotic and endoplasmic reticulum stress in plants. Autophagy is a crucial and evolutionarily conserved process that breaks down and recycles damaged or unnecessary cytoplasmic components. This process is essential for plant growth and for responding to environmental stresses. In this study, we investigated how autophagy is regulated during osmotic stress in Arabidopsis thaliana, with a focus on the behavior of the RFP-tagged ATG8i protein and the potential role of cytosolic Ca2⁺ in this process. Osmotic stress was induced with sorbitol and Ca2+ accumulation was monitored with a Cameleon transgenic line. Ca2⁺ influx from the apoplast was disrupted using EGTA, and autophagy was analyzed in a transgenic line expressing RFP-ATG8i under its native promoter. We found that osmotic stress triggers Ca2⁺ accumulation, with a pronounced response in the hypocotyl-root transition zone and a weaker response at the root tip. Both osmotic stress and Ca2⁺ signaling promote the accumulation of RFP-ATG8i-labeled autophagosomes in predominantly in hypocotyl-root transition zone. Furthermore, analysis of GFP-HDEL/RFP-ATG8i doubled transgenic line revealed colocalization of RFP-ATG8i with the endoplasmic reticulum marker HDEL, suggesting that ATG8i participates in reticulophagy and may contributed to the ER turnover under stress conditions.
The antiviral protein MORC3 is frequently inhibited by viruses. To counteract viral antagonism, MORC3 represses a noncanonical pathway of type-I-interferon (IFN) such that viral inhibition of MORC3 triggers ( > 10,000-fold) IFN induction. How MORC3 represses this pathway, and why IFN induction upon MORC3 loss is so potent without canonical IRF3/7 transcription factors, is unknown. Here, we show that MORC3 restricts chromatin accessibility at tandem repeat elements harboring up to 61 homotypic transcription factor motifs. One such element becomes a potent enhancer of IFNB1 upon MORC3 loss. Its motif cluster contains 45 PU.1 binding sites and is necessary and sufficient for MORC3-mediated repression and enhancer activity upon MORC3 loss. PU.1 recruits MORC3 to repress this enhancer by recruiting DAXX and enabling H3.3 incorporation. Upon MORC3 loss, PU.1 drives IRF3/7-independent IFN induction. Other restricted tandem repeats contain homotypic motif clusters of SPI, AP-1, and SP/KLF transcription factors. Our findings uncover a TF motif cluster-driven repression mechanism by MORC3 at tandem repeats, enabling specific repression of an IFNB1 enhancer such that viral antagonism of MORC3 induces interferon.
Monitoring therapeutic response is essential for improving the precision and efficacy of photodynamic therapy (PDT), yet quantitative and real-time evaluation remain challenging. Herein, we report a programmable DNA nanotube-based dual-mode biosensing platform for monitoring PDT-induced apoptosis through complementary fluorescence and electrochemical signals. In this system, methylene blue (MB) functions as a multifunctional component, simultaneously acting as a photosensitizer, near-infrared imaging probe, and electrochemical reporter. A caspase-3-responsive peptide is integrated into the DNA nanotube scaffold, enabling apoptosis-triggered fluorescence activation. Caspase-3 activation triggers peptide cleavage, resulting in fluorescence recovery and enhanced electrochemical signals, with limits of detection (LOD) of 0.786 ng/mL for the fluorescence method and 0.622 ng/mL for square-wave voltammetry (SWV). Gold nanoparticles incorporated into the DNA nanotube further catalyze endogenous H2O2 decomposition to generate oxygen, alleviating tumor hypoxia and enhancing PDT efficacy. The platform demonstrated accurate dual-mode detection capability in complex biological samples. These results demonstrate that the programmable DNA nanotube-based platform enables synchronized electrochemical and fluorescence biosensing through a shared caspase-3-responsive mechanism, thereby allowing real-time therapeutic feedback during photodynamic therapy.
Obesity stems from a chronic imbalance between energy intake and expenditure. Current therapeutic strategies primarily focus on reducing caloric intake, yet their long-term efficacy is often limited by compensatory metabolic adaptations that lead to weight regain. This review outlines the neural mechanisms through which the central nervous system regulates appetite and the peripheral metabolic pathways that drive adipose thermogenesis. Furthermore, it examines how integrated approaches-spanning from approved to preclinical and clinical-stage investigational agents (e.g., dual- or multi-target agonists), microbiome-targeted interventions (e.g., probiotics), and exercise therapy-can synergistically overcome the limitations of single-pathway strategies. Ultimately, this review provides a theoretical foundation for designing next-generation, personalized, multimodal obesity management regimens. Traditional weight-loss drugs primarily act by centrally suppressing appetite, reducing food intake through modulation of neural circuits in regions such as the hypothalamus. However, studies show that relying on appetite suppression often triggers compensatory metabolic adaptation, ultimately leading to weight regain. Current anti-obesity drug development is therefore shifting toward integrated central-peripheral dual mechanisms. GLP‑1/glucagon dual-receptor agonists and triple-receptor agonists (such as retatrutide) have exhibited unprecedented weight-loss efficacy in clinical trials. These novel agents overcome the limitations of single-target appetite suppression by synergistically integrating central anorexigenic signaling with peripherally mediated increases in energy expenditure, thereby achieving more potent and durable weight reduction. The sustainability of obesity treatment relies on a dual-pronged intervention strategy: suppressing appetite to reduce energy intake while actively promoting energy expenditure, thereby overcoming the metabolic adaptation and weight rebound associated with monotherapy.
Diabetic retinopathy (DR) and retinal aging, though arising from distinct causes, share converging mechanisms-including oxidative stress, chronic inflammation, mitochondrial dysfunction, and AGE accumulation-that compromise retinal integrity. These overlaps suggest common gene expression patterns, and highlight the contribution of disease-associated or accelerated aging processes to diabetes-induced retinal injury. We systematically retrieved DR- and aging-related human genes from public genetic databases, identified their overlap, and focused on those involved in key metabolic pathways (AGEs, oxidative stress, lipid metabolism, and autophagy). Genes were then cross-validated across multiple databases and filtered by ocular expression to ensure relevance to retinal pathology. Our findings show that although DR and retinal aging arise from distinct etiologies, they converge on four principal metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and impaired autophagy-that collectively drive similar vascular, neuronal, and inflammatory injury within the retina. Shared genes with high ocular expression reinforce the biological relevance of these pathways, while multi-pathway hub genes appear to function as central regulators that integrate redox imbalance, metabolic disruption, and proteostatic failure. These results provide a unified molecular perspective of retinal degeneration and support the potential development of therapeutic approaches designed to simultaneously target age- and diabetes-associated retinal pathology. This review suggests that DR and retinal aging, although initiated by distinct triggers, converge on shared metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and autophagy impairment-mediated by genes expressed in ocular tissues. Within these intersecting pathways, shared hub genes emerge as central control nodes that may amplify molecular dysfunction and represent potential therapeutic entry points. By mapping these molecular intersections, this study may provide a unified mechanistic perspective of retinal degeneration and support the development of dual-purpose strategies aimed at preventing or mitigating both DR and aging-related retinal decline. These findings highlight potential translational opportunities for targeting shared metabolic networks; however, they should be interpreted as hypothesis-generating and require further experimental and clinical validation to establish causal relationships and therapeutic relevance.
The anaerobic co-digestion (AcoD) of food waste (FW) and biodegradable plastics (BPs) is a promising waste-to-energy strategy, yet it remains severely bottlenecked by asynchronous hydrolysis. Overcoming this limitation via traditional trial-and-error optimization is prohibitively slow and expensive. To address this, an integrated machine learning (ML) framework was developed, coupling predictive modeling with rigorous experimental and mechanistic validation. Virtual screening initially identified mesophilic enzyme-loaded biochar (BC) as the optimal intervention. Consequently, a novel proteinase K-loaded BC (PKBC) was synthesized, which successfully achieved up to 90% degradation of 2-mm BPs films in a 120-day trial. A high-precision random forest model further mapped the system dynamics, confirming that degradation is positively driven by reaction time and methane yield, but tightly constrained by larger particle sizes. Providing a fundamental basis for these predictions, multi-omics analyses revealed that PKBC triggers a targeted metabolic cascade. This cascade reprograms the microbial community to accelerate lactate-driven BPs cleavage and maximize hydrogenotrophic methanogenesis. Ultimately, this work delivers a highly efficient solution for mixed waste treatment and establishes a transferable AI-first paradigm for the intelligent design of complex bioprocesses.
Endometriosis defined by the growth of endometrial tissues outside the uterus, affects women of reproductive age. A critical process in endometriosis progression, angiogenesis involves endothelial cell migration, proliferation and tube formation, with vascular endothelial growth factor (VEGF) playing a powerful role. Exposure to endocrine-disrupting pollutants, like Hexachlorobenzene (HCB) andChlorpyrifos (CPF), is linked to a higher risk of reproductive diseases including endometriosis. Both HCB and CPF are weak aryl hydrocarbon receptor (AhR) ligands. These study examined HCB and CPF mechanisms of action in endometriosis-associated angiogenesis in vitro. Our results show that HCB (0.005, 0.05 and 5 μM) and CPF (0.5-50 μM) induced VEGF secretion in human stromal endometrial cells (T-HESCs). Moreover, HCB- or CPF-conditioned media (HCB-CM, CPF-CM) from T-HESCs boosted endothelial cell (EA.hy926) proliferation and survival. In addition, wound healing assays rendered an increase in EA.hy926 cell migration after exposure to HCB-CM (0.005-0.5 μM) or CPF-CM (5 μM), while tube-like structures revealed an increase in neovasculogenesis after HCB-CM (0.5 μM) or CPF-CM (5 μM). Our findings show that HCB- and CPF-induced angiogenesis was mediated by AhR and VEGF receptor-2. These results demonstrate that both pesticides increase VEGF secretion in endometrial cells and triggers angiogenesis, a critical event in endometriosis progression.
Recently, ferroptosis has emerged as a pathogenic mechanism that drives metabolic dysfunction-associated steatohepatitis (MASH); however, the upstream triggers and their relevance to fibrosis remain poorly understood. Here we identified dietary cholesterol-induced ferroptosis and the downregulation of peroxisome proliferator-activated receptor delta (PPARδ) as central drivers of MASH pathogenesis. To investigate this, human liver samples and cholesterol-enriched dietary murine models of MASH were examined in parallel with mechanistic studies in hepatocytes and hepatic stellate cells (HSCs). Cholesterol-induced MASH was associated with pronounced hepatic lipid peroxidation and the selective downregulation of PPARδ. The loss of PPARδ disrupted redox homeostasis and sensitized hepatocytes to ferroptosis, whereas exosomal double-stranded DNA released from ferroptotic hepatocytes activated STING-TBK1-IRF3 and induced expression of profibrotic genes in HSCs. These effects were reversed by either overexpression of hepatocyte-specific PPARδ or pharmacologic treatment with DN203316, a novel and highly selective PPARδ agonist. In vivo, DN203316 mitigated ferroptosis, inflammation and fibrosis without inducing metabolic derangement. These findings were substantiated by clinical data demonstrating a marked increase in lipid peroxidation and STING-driven HSC activation in liver tissues from patients with MASH. In conclusion, PPARδ is a key regulator of cholesterol-induced ferroptosis and exosome-mediated fibrogenic signaling in MASH. DN203316 offers a promising therapeutic strategy to suppress ferroptosis, disrupt hepatocyte-HSC crosstalk and attenuate disease progression.
Cellular decision-making relies on the integration of multiple extracellular cues into coordinated functional responses. Synthetic biology provides tools to rewire this process by engineering receptors that convert defined inputs into programmable outputs. Here, we describe a synthetic receptor-based architecture that enables monocytic-like cells to sense an immune-regulatory ligand and conditionally activate a phagocytic program. We engineered a synthetic Notch-based receptor (SNIPR) that detects programmed death-ligand 1 (PD-L1), a broadly expressed immune-regulatory ligand. Upon PD-L1 engagement, the circuit triggers programmable outputs, including expression of a fluorescent reporter or CV1-Fc, as model effector that interferes with CD47-mediated inhibition of phagocytosis. We show that circuit activation scales with PD-L1 levels, partially attenuates PD-1/PD-L1 signaling, and that conditional CV1-Fc expression enhances engulfment of SKOV-3 ovarian cancer cells by THP-1-derived macrophages in vitro. Collectively, this work reframes PD-L1 from an end-point therapeutic target to a programmable input signal for synthetic circuit activation and establishes a modular framework for ligand-responsive control of engineered macrophage behaviour.
Intrusive thoughts and repetitive behaviors are hallmark features of obsessive-compulsive disorder (OCD). Acute stress is closely associated with the onset and severity of obsessive-compulsive symptoms, but the underlying mechanisms remain largely unclear. Recent studies have implicated the nucleus accumbens (NAc) in the interaction between stress and compulsive behaviors. In this study, we used Sapap3 knockout (KO) mice, a validated model of compulsive grooming, to examine how acute restraint stress (ARS) influences compulsive behaviors and their neural correlates. Compared with wild-type controls, KO mice displayed a significant stress-dependent increase in grooming behavior following ARS. This behavioral enhancement was accompanied by elevated population activity of NAc neurons, as revealed by in vivo calcium imaging. Furthermore, Sapap3 KO mice exhibited markedly reduced D2 receptor protein expression in the nucleus accumbens. Both optogenetic inhibition of D2 receptor-expressing medium spiny neurons (D2-MSNs) and pharmacological activation of D2 receptors with bromocriptine significantly attenuated acute restraint stress-induced compulsive grooming. These findings suggest that acute stress exacerbates compulsive behavior in Sapap3 KO mice, likely via further impairing D2 receptor function in the NAc, highlighting the critical role of NAc D2 receptors and D2-MSN activity in stress-triggered obsessive-compulsive symptoms.
Sepsis remains a major clinical challenge characterized by immune dysregulation and coagulopathy. Ursodeoxycholic acid (UDCA) has been suggested to confer benefit in sepsis, but its mechanism remains unclear. This study explored whether UDCA modulates platelet function during sepsis via triggering receptor expressed on myeloid cells 2 (TREM2), an immunoreceptor with an emerging role in platelet biology. We employed an integrated strategy combining a retrospective cohort of 6476 sepsis patients (MIMIC-IV) with exploratory causal mediation analysis, mechanistic studies in LPS-induced septic and TREM2-knockout mice, computational docking suggesting a potential interaction between UDCA and TREM2, and a prospective pilot study in 8 septic patients receiving UDCA. Retrospective analysis showed that UDCA was associated with reduced hospital mortality (total effect -0.2287, P < 0.001), with 69.8% of this association mediated by increased platelet counts (natural indirect effect -0.1597, P < 0.001). Mechanistically, LPS downregulated platelet TREM2 and increased Syk-PI3K-Akt phosphorylation, accompanied by platelet hyperactivation. UDCA was associated with increased TREM2 expression and attenuated downstream signaling, and these effects were attenuated or not observed in TREM2-knockout mice. In the pilot clinical study, UDCA increased platelet counts (from 161.6 ± 106.2 to 211.4 ± 100.1 × 109/L, P = 0.001) and selectively inhibited ADP-induced aggregation (from 49.23 ± 20.45% to 31.63 ± 26.28%, P = 0.001) without significantly altering global coagulation parameters. In conclusion, these findings suggest that UDCA may be associated with improved sepsis outcomes by modulating platelet homeostasis in a TREM2-associated manner, providing preliminary translational support for TREM2 as a potential target in sepsis-associated coagulopathy.
The ipsilateral silent period (iSP) is used to study interhemispheric control of voluntary motor output. It involves a brief suppression of electromyographic (EMG) activity in a muscle during isometric contraction, triggered by Transcranial Magnetic Stimulation (TMS) over the ipsilateral primary motor cortex (M1). The aim of this study was to investigate cortical activity associated with iSP. The study involved 28 healthy right-handed volunteers who performed maximal contractions of the left hand (unimanual) or both hands (bimanual) across conditions with and without TMS. We combined TMS to left M1 with functional Near-Infrared Spectroscopy (fNIRS) over the right hemisphere. EMG was recorded from the hand muscles to quantify the iSP. A significantly greater normalized iSP area was found in the TMS bimanual condition compared to the unimanual one, with a strong correlation between the two. fNIRS revealed higher oxyhemoglobin (HbO) concentration changes in the No TMS condition than in the TMS conditions. Specifically, TMS induced HbO decreases in motor, prefrontal, premotor, parietal, and temporal areas. Reductions in premotor and parietal areas correlated with M1 activity decrease only in unimanual condition. In TMS conditions, a positive correlation was found between fNIRS HbO values in associative parietal cortex and the normalized iSP area: the higher the HbO concentration changes, the greater the inhibition. These findings show reduced M1 activity and demonstrate that a broader frontoparietal network is influenced by the transcallosal motor output. These findings contribute to a better understanding of interhemispheric inhibition and may have implications for the study of neurological disorders.
Fatigue is a prevalent and disabling symptom in Sjögren's disease (SjD), yet its pathogenesis remains poorly understood and inadequately managed. This narrative review addresses a critical gap in knowledge by conceptualizing SjD-related fatigue as a bidimensional phenomenon driven by both biomedical and psychosocial mechanisms, and framed within the model of persistent somatic symptoms (PSS). In this narrative review, findings from immunology, neuroendocrinology, psychology, and clinical research were synthesized to examine predisposing, triggering, and maintaining factors contributing to SjD-related fatigue. Particular attention was given to studies exploring immune dysregulation, neuroimmune signaling, autonomic imbalance, and psychological traits. Findings indicate that biomedical contributors-such as pro-inflammatory cytokine (e.g., interleukin [IL]-1β, IL-36α), neuroendocrine dysfunction, dysbiosis, and genetic predispositions-interact with psychosocial vulnerabilities, including early-life adversity, personality profiles, maladaptive coping strategies, and mood disorders. These interactions foster self-reinforcing loops of symptom persistence. Notably, current treatments targeting isolated domains yield limited success. Nonetheless, integrated strategies-ranging from biologics and cytokine modulators to exercise, cognitive behavioral therapy, and neuro-modulatory interventions-have demonstrated promise, particularly when aligned with the PSS framework. This narrative review underscores the need for a paradigm shift in fatigue management, advocating for multidimensional assessment and personalized, multimodal interventions. By illuminating the duality of SjD-related fatigue, this narrative review provides a roadmap for more effective diagnosis, research, and patient-centered care.
Polybromo 1 (PBRM1), encoding the BAF180 subunit of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is commonly lost or mutated across malignancies. Despite its prevalence, tailored therapeutics for PBRM1-defective cancers remain limited. PBRM1 loss is associated with elevated replication stress and DNA damage responses, implying dependence on compensatory repair pathways. Given the lack of genotype-matched drugs, exploiting DNA-repair dependencies may provide a precision option for PBRM1-deficient disease. We pursued a synthetic-lethality strategy in colorectal cancer to test whether clinically used PARP inhibitors selectively suppress PBRM1-deficient cells and to define the linked cell-cycle and stress-response mechanisms. We also compared PARP inhibition with broader chromatin-remodeler targeting. Isogenic PBRM1-/- HCT116 colorectal carcinoma cells were generated by CRISPR/Cas9 lentiviral editing using sgRNAs cloned into lenti-CRISPR-V2. Knockout was confirmed by Western blotting, Sanger sequencing, and RT-qPCR. A focused compound screen compared four agents PARP inhibitors olaparib and rucaparib, the multi-target chromatin remodeler inhibitor AU-24,118, and the SMARCA2/4-targeting degrader AU-1530 using dose-response CCK-8 viability assays and selectivity indices. We then validated our results by 12-day colony-formation assays. Mechanistic analyses measured drug-induced G2/M accumulation by propidium iodide staining and flow cytometry and quantified apoptosis by Annexin V/PI dual staining, with significance assessed by t-test or two-way ANOVA. PBRM1 loss confers selective hypersensitivity to PARP inhibitors, which intensify DNA-damage signaling, promote G2/M checkpoint arrest, trigger apoptosis, and induce stress-response genes such as CSRNP3. Although this effect appears context-dependent and was not observed uniformly across all PBRM1-/- models tested. These results support further evaluation of PBRM1 as a potential predictive biomarker in defined molecular contexts rather than as a universal marker of PARP inhibitor sensitivity.