Pathogenic bacteria continue to pose a severe and persistent threat to global public health, necessitating the development of rapid, sensitive, and reliable detection systems. Bacteriophages (phages), owing to their exquisite host specificity and biological robustness, have emerged as powerful biorecognition elements in biosensor development. This review provides a systematic analysis of recent advances in phage-based biosensing, with a particular emphasis on their modular design. We first discuss three fundamental phage-based recognition strategies for sensor construction: immobilization-based capture, phage amplification, and reporter phage systems. The application of synthetic biology tools, such as CRISPR genome editing and directed evolution, alongside interface engineering strategies, such as site-specific immobilization is discussed to precisely regulate the phage-sensor interface and enhance biosensor performance. Various signal transduction platforms, ranging from label-free techniques to reporter-based amplification are summarized, and their roles in translating biological recognition into quantifiable outputs are described. The convergence of phage engineering and computational tools for next-generation biosensor design is highlighted, particularly within a design-build-test-learn framework. Finally, we explore future directions, including AI-assisted phage design, theranostic applications, and the transition toward programmable, adaptive biosensing systems, aiming to establish intelligent platforms for precise clinical diagnosis and on-site environmental monitoring.

Abstract Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor outcomes, particularly among older adults and patients harboring adverse-risk features such as FLT3-ITD and p53 mutations. Relapsed or refractory (R/R) AML remains largely incurable, underscoring the urgent need for new therapies that selectively target leukemia-specific survival pathways while sparing normal hematopoiesis. Through a focused medicinal chemistry campaign, we optimized an understudied thioxanthenone chemotype and identified 06-30 as a potent lead compound with broad anti-AML activity. 06-30 induces robust and selective cytotoxicity across genetically diverse AML cell lines including models resistant to standard of care agents (cytarabine, azacitidine), and demonstrates strong activity in primary AML blasts with adverse molecular profiles. Unbiased integrative proteomic and transcriptomic analyses revealed p47phox (NCF1), a cytosolic organizer subunit of the NADPH oxidase complex, as the top common drug-induced target following 06-30 treatment with >9-fold increases in protein abundance and >50-fold increases in mRNA levels. Although p47phox is well established in host defense and inflammatory reactive oxygen species (ROS) generation, its role in AML pathogenesis and therapeutic sensitivity remains undefined. We hypothesize that p47phox functions as a pharmacodynamically regulated effector of 06-30 that drives ROS-mediated DNA damage and apoptosis in AML by exploiting leukemia-specific redox dysregulation. Supporting this hypothesis, shRNA-mediated silencing of p47phox significantly diminished 06-30-induced ROS generation and apoptosis and antioxidant co-treatment similarly blunted cell death. Importantly, 06-30 demonstrated selective toxicity toward AML cells while sparing normal CD34+ bone marrow progenitors, consistent with the enhanced antioxidant capacity of normal hematopoietic cells and establishing a clear therapeutic window. In vivo, 06-30 significantly extended overall survival and was very well tolerated. Ex vivo analyses demonstrated that its antileukemic efficacy was associated with increased p47phox expression and oxidative DNA damage as quantified by 8-oxoguanine levels. To our knowledge, no anticancer pharmacologic activators of p47phox have been previously described. Thus, thioxanthenone 06-30 represents both a first-in-class mechanistic probe and a promising therapeutic lead for redox-based targeting in AML. Together, these findings provide strong rationale for the further preclinical development and eventually clinical investigation of 06-30 as a strategy to exploit redox vulnerabilities in leukemia and improve outcomes for patients with limited therapeutic options. Citation Format: Madison Gamble, Claudia M. Espitia, Sruthi Sureshkumar, Natalie Hakim, Kevin R. Kelly, Wei Wang, Steffan T. Nawrocki, Jennifer S. Carew. A novel thioxanthenone activates p47phox to exploit redox vulnerabilities in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4585.

Precisely manipulating the coordination environment in single-atom nanozymes (SAzymes) remains a critical challenge in breaking the intrinsic activity ceiling, thus limiting the multifunctionality of current enzyme-mimetic catalysts. In this study, iridium SAzymes featuring an asymmetric Ir-N3S1 coordination motif (Ir-S/N-C) were prepared by adding sulfur to a traditional Ir-N-C framework. Density functional theory calculations revealed that this symmetry-breaking coordination design enabled the fine modulation of the local electronic structure of the isolated iridium centers, which upshifted the d-band center and substantially reduced the energy barrier for O2 activation. Ir-S/N-C exhibited markedly enhanced oxidase- and peroxidase-like activities, and a glutathione-oxidase-like functionality emerged, thus achieving integrated multienzyme-like catalysis within a single-atom platform. Notably, the strong intrinsic oxidase activity allowed the construction of a self-sufficient H2O2-free colorimetric sensing system for antioxidants and organophosphate pesticides, delivering high sensitivity and selectivity in complex sample matrices. Overall, this study demonstrated asymmetric sulfur coordination as a promising coordination-engineering strategy for modulating the electronic structure of single-atom sites and highlighted its effectiveness in developing high-performance multifunctional SAzymes.

Acute myeloid leukemia (AML) is a heterogeneous and devastating hematologic malignancy characterized by differentiation blockage and immature progenitor accumulation, positioning differentiation therapy as a promising therapeutic strategy. However, clinical success is largely confined to acute promyelocytic leukemia (APL) and isocitrate dehydrogenase (IDH)-mutated AML, leaving most AML subtypes with unmet needs. Herein, novel noscapine derivative ES428 is discovered that induces AML differentiation and exhibits potent anti-AML efficacy across diverse AML cell lines, primary patient samples, as well as cell line- and patient-derived xenograft models. Target deconvolution with combinatorial strategies identifies dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in de novo pyrimidine synthesis, as the direct functional target. Integration of molecular dynamics simulations and comprehensive structure-activity relationship studies elucidates ES428’s unique mechanism via simultaneous engagement with DHODH and mitochondrial membrane lipids. This dual-engagement underpins ES428’s enhanced target engagement, efficacy, and selectivity in physiologically relevant mitochondrial membrane environment, potentially through stabilizing ES428-DHODH interaction in situ and facilitating ES428’s selective mitochondrial localization. Furthermore, ES428 triggers a mechanistic cascade linking decreased pyrimidine synthesis, reduced O-linked N-acetylglycosylation (O-GlcNAcylation), EP300/CREBBP catalytic inhibition, and transcriptional reprogramming. Our findings identify promising lead candidates, establish a novel DHODH-targeting strategy, and provide important mechanistic insights to advance differentiation therapies for myeloid malignancies.

Abstract Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy characterized by the accumulation of immature myeloid blasts that disrupt hematopoiesis. Although initial remissions can be achieved with standard chemotherapy, relapse is frequent and durable responses remain uncommon. This underscores the need for new therapeutic strategies that can overcome established resistance mechanisms. Disruption of epigenetic homeostasis is a common feature of AML pathogenesis and offers an opportunity for targeted therapy. Histone deacetylase (HDAC) inhibitors are one class of agents that induce epigenetic reprogramming and have previously demonstrated antileukemic activity. However, their efficacy is blunted by the activation of cytoprotective autophagy. Simultaneous blockade of HDAC activity and autophagic flux therefore represents a rational approach to enhance therapeutic benefit. To address this, we developed H11, a first-in-class bifunctional small molecule engineered to concurrently inhibit HDACs and suppress autophagy. H11 potently reduced viability and triggered apoptosis across genetically diverse AML models and primary AML specimens from patients including those with adverse features such as FLT3-ITD and loss of p53 function. H11 retained potent activity in models resistant to frontline therapies, indicating its potential to overcome both epigenetic and lysosomal-mediated resistance mechanisms. Importantly, H11 demonstrated strong therapeutic selectivity with very limited effects against normal CD34+ bone marrow progenitors. Mechanistic studies demonstrated robust HDAC inhibition, evidenced by increased global histone acetylation, coupled with impaired autophagic degradation, reflected by p62 accumulation, lysosomal deacidification, and blocked autophagic flux. H11 treatment also decreased the expression of the oncogenic transcription factor c-Myc and increased CDKN1A (p21), consistent with epigenetic reprogramming and disruption of AML survival circuitry. Because epigenetic dysregulation is a hallmark of AML, we next evaluated H11 in combination with the FDA-approved hypomethylating agent azacitidine (AZA). The H11-AZA combination produced strong synergy, markedly enhancing cytotoxicity across multiple AML cell lines and significantly extending overall survival in an orthotopic FLT3-ITD+ mouse xenograft model of AML. Together, these findings establish H11 as a first-in-class dual HDAC-autophagy inhibitor that integrates epigenetic modulation with autophagy suppression to promote apoptosis and disrupt adaptive AML survival pathways. This coordinated mechanism of action highlights H11 as a promising next-generation therapeutic with strong potential to improve clinical outcomes in patients with AML. Citation Format: Natalie L. Hakim, Claudia M. Espitia, Sruthi Sureshkumar, Madison Gamble, Bi Fangchao, Wei Wang, Kevin Kelly, Jennifer S. Carew, Steffan T. Nawrocki. H11 is a first-in-class bifunctional HDAC and autophagy inhibitor with potent antileukemic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4506.

Repurposing FDA approved drugs with off-target autophagy inhibition such as chloroquine/hydroxychloroquine (CQ, HCQ) has produced modest anticancer activity in clinical trials, due in part, to a failure to define predictive biomarkers that enable the selection of patients that best respond to this treatment strategy. We identified a new role for REDD1 as a determinant of sensitivity to autophagy inhibition in renal cell carcinoma (RCC). RNA sequencing, qRT-PCR, immunoblotting, gene silencing, knockout and overexpression studies revealed that REDD1 expression is a key regulator of cell death stimulated by autophagy inhibitors. Comprehensive in vitro and in vivo studies were conducted to evaluate the selectivity, tolerability, and efficacy of the PIM kinase inhibitor TP-3654 and CQ in preclinical models of RCC. Markers of autophagy inhibition and cell death were evaluated in tumor specimens. Transcriptomic analyses identified REDD1 (DDIT4) as a highly induced gene in RCC cells treated with the PIM kinase inhibitor TP-3654. Focused studies confirmed that PIM1 inhibition was sufficient to induce REDD1 and stimulate autophagy through the AMPK cascade. DDIT4 knockout and overexpression studies established its mechanistic role as a regulator of sensitivity to autophagy inhibition. Inhibition of autophagy with CQ synergistically enhanced the in vitro and in vivo anticancer activity of TP-3654. Our findings identify REDD1 as a novel determinant of the sensitivity of RCC cells to autophagy inhibition and support further investigation of PIM kinase inhibition as a precision strategy to drive sensitivity to autophagy-targeted therapies through REDD1 upregulation.

Increased basal protein synthesis activity is a hallmark feature that distinguishes many types of malignant cells from their normal counterparts. The survival and proliferation of cancer cells are tightly linked to functional unfolded protein response (UPR) and endoplasmic reticulum (ER)-associated degradation (ERAD) pathways due to their high rates of protein synthesis. The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP)/p97 facilitates the extraction of proteins from organelles, chromatin, and protein complexes to target them for ubiquitin–proteasome system (UPS)-mediated degradation. p97 plays a key role in protein quality control and in the maintenance of protein homeostasis through its regulation of ERAD. The disruption of p97 activity leads to an accumulation of undegraded proteins, triggers the UPR, and can culminate in proteotoxic cell death. Given this, p97 inhibition offers an opportunity to selectively kill cancer cells that exhibit high basal protein synthesis rates. This review explores p97’s molecular structure, diverse cellular roles, and clinical potential with a particular focus on CB-5083 and CB-5339, the only p97 inhibitors to date that have advanced into clinical trials. We discuss their mechanisms of action, clinical trial outcomes, and the transformative potential of rational combination strategies to maximize their therapeutic potential. By integrating foundational biological insights with translational perspectives, we highlight p97 as a precision target for cancer treatment.

Background: Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass and increased fracture risk. Emerging evidence indicates that the chemotherapeutic agent doxorubicin (DOX) significantly disrupts bone remodeling homeostasis. This study employed an integrative computational approach to uncover the mechanisms underlying DOX-associated OP pathogenesis. Methods: Network toxicology was used to screen molecular targets in DOX-induced OP and establish protein-protein interaction (PPI) networks. The biological roles of hub genes were explored through KEGG pathway and GO analyses. Three machine learning algorithms (support vector machine-recursive feature elimination (SVM-RFE), random forests (RF), and LASSO regression) were applied to identify core genes involved in OP pathogenesis. Molecular docking studies were used to characterize the binding potential of DOX with OP-related core targets. Results: A total of 198 overlapping candidates were identified by intersecting the 8297 candidate targets of DOX with 816 OP-associated targets. Through PPI analysis, the top 20 hub genes were determined by both maximal clique centrality (MCC) scoring and degree centrality, with 16 genes common to both centrality measures. The 16 hub genes were associated with the Jak-STAT (P=9.1x10(-4)) and IL-17 (P=1.7x10(-4)) signaling pathways. Machine learning identified six OP-associated core candidates: IL13, ZWINT, RRM2, PCNA, TYMS, and CD34. DOX exhibited high-affinity binding to IL13, RRM2, PCNA, and TYMS (Delta G < -7.0 kcal/mol). Conclusion: This study suggests that DOX may induce OP through synergistic dysregulation of inflammatory and proliferative pathways, providing testable hypotheses for understanding chemotherapy-induced bone loss.

The endoplasmic reticulum (ER) is the largest organelle in eukaryotic cells, and it plays a crucial role in regulating various biological processes, including protein folding, translation, and structural maturation. Accurate protein modification is essential for maintaining oxidative stress, apoptosis, and cellular senescence in the organism. The regulation of protein homeostasis involves three biological processes: endoplasmic reticulum stress (ERS), endoplasmic reticulum autophagy (ERPA), and endoplasmic reticulum-associated degradation (ERAD). Retinal degenerative disease (RDD) is a blinding eye conditions that cause severe vision loss. Although the pathogenesis of RDD is complex, previous data suggest that ER plays a key role in the development of a variety of eye diseases, such as diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), and axial myopia. Based on this, this paper will review the process of endoplasmic reticulum quality control (ERQC) and summarize the pathological mechanisms of the aforementioned eye diseases from the perspective of ERQC, providing new insights for the treatment of RDD.

Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC50, SMS2 = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t1/2, cornea = 1.11 h; t1/2, meibomian glands = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

The development of dual prostaglandin E2 receptors 2/4 (EP2/EP4) antagonists represents an attractive strategy for cancer immunotherapy. Herein, a series of 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives with potent EP2/EP4 dual antagonism were discovered by fine-tuned structural modifications. The biphenyl side chain was found to be the key pharmacophore for the transition from EP4 antagonism to EP2/EP4 dual antagonism. The introduction of large sterically hindered segments posed challenges on obtaining EP2 potency, while having minimal impact on EP4 potency. Molecular dynamics simulations verified that the EP2 pocket is relatively narrow compared to EP4, and the key residues surrounding the EP2 pocket impose spatial restrictions on the entry of antagonists. Representative compound 29 (CZY-1068) significantly reduced PGE2-induced expression of immunosuppression-related genes in macrophages. Notably, compound 29 elicited robust antitumor efficacy in the syngeneic MC38 tumor model. Taken together, this study provides a proof-of-concept for obtaining novel potent dual EP2/EP4 antagonists based on rational structural modifications.

The palladium-catalyzed asymmetric allylic alkylation of carbon-based pronucleophiles is a highly efficient and enantioselective strategy for the synthesis of pharmaceutically relevant molecules. While significant progress has been made in the...

Deuterium labeling is increasingly important across scientific fields, from drug development to materials engineering, but current methods often require expensive catalysts. Here we demonstrate a simple, photocatalyst-free approach for incorporating deuterium into organic molecules using visible light. By employing common thiol compounds under mild blue-light irradiation (380-420 nm), we successfully modify two key chemical groups (formyl and α-amino) with high efficiency (up to 96% deuterium incorporation). This method eliminates the need for specialized PCs, significantly reducing costs and complexity. Surprisingly, we find that the system generates reactive intermediates (thiyl radicals and hydrogen atoms) through previously unrecognized light-activated pathways. These discoveries challenge conventional assumptions about photochemical deuteration and offer practical advantages for both laboratory research and industrial-scale production. Our results provide a more sustainable and scalable route to deuterated compounds while opening possibilities for light-driven chemistry without expensive catalysts. This work advances isotope labeling technology and suggests broader applications for simple, light-powered reactions in chemical synthesis.

Inhibiting ferroptosis represents a promising strategy to combat ferroptosis-related diseases. Here we show that 428, a selenide-containing noscapine derivative, effectively inhibits ferroptosis in various cell lines by enhancing the stability and activity of GPX4. TRIM41 was identified as a novel E3 ubiquitin ligase of GPX4 and 428 was demonstrated to bind to the selenocysteine residue Sec46 of GPX4 via the formation of a transient and reversible Se-Se bond, thereby blocking the interaction between GPX4 and TRIM41, stabilizing GPX4 and enhancing its activity. This unique dynamic covalent binding mode was preliminarily validated by structure-activity relationship analysis and molecular docking studies. Importantly, we demonstrated that 428 treatment alleviates bleomycin-induced pulmonary fibrosis in vivo by inhibiting ferroptosis. Overall, our studies identified a novel stabilizer and activator of GPX4, offering a potential therapeutic approach for the treatment of ferroptosis-related diseases and uncovering a new mechanism for regulating GPX4 degradation.

Based on our previous explorations of o-diiodoarene/NaH as a novel aryne-generation system, herein we present an efficient route for the divergent synthesis of 1,3,5-trisubstituted benzenes. Since carboxylic acid could be converted into a lot of functional groups, in this protocol, the readily available and inexpensive 2,3,5-triiodobenzoic acid (TIBA) was employed as the starting material for the preparation of diverse aryne precursors. With this aryne-generation toolbox, a series of transformations were achieved between various nucleophiles and these aryne precursors, producing 5-iodo-1,3-disubstituted benzenes as valuable intermediates. The subsequent Ullmann reaction then gave hetero-1,3,5-trisubstituted benzenes.

Ethnopharmacological relevance: Siraitia grosvenorii (S. grosvenorii) is a traditional herbal medicine employed for the prevention of lung diseases. Mogrosides and flavonoids are postulated to be the principal active components. Nevertheless, the dynamic distribution of its active components in vivo and the amount of accumulation in the lung target tissue remain indistinct. Aim of the study: This study investigates the dynamic distribution patterns of 9 bioactive components within the extract of S. grosvenorii in rat blood, heart, liver, spleen, lung, and kidney, along with its pulmonary targeting. Materials and methods: The blood, heart, liver, spleen, lung, and kidney samples of rats were obtained at diverse time points after oral administration of S. grosvenorii decotion, and a UPLC-MS/MS method was developed to determine the contents of 9 bioactive components (Siamenoside I, Grosvenorine, 11-O-Mogroside V, Mogroside II-E, Mogroside III-E, Mogroside IV-A, Mogroside V, Mogroside VI and Kaempferitrin) within the samples. The concentration-time curves of each component in each sample were plotted and the pharmacokinetic parameters were computed. Results: The AUC0 ->infinity and Cmax of 9 bioactive components in lung tissue were conspicuously higher than those in heart, liver, spleen, and kidney. For instance, the AUC0 ->infinity of Mogroside V in lung tissue was 7.20-55.54 times higher than that in blood and other tissues, and the Cmax in lung tissue was 3.315-96.70 times higher than that in blood and other tissues. The lung target efficiency of 9 bioactive components ranged from 1.885 to 15.80, indicating that the active components of S. grosvenorii exerting pharmacological effects are highly concentrated in the lung target tissue. The Tmax of 9 bioactive components in blood was within the range of 10.20-100.2 min, while the Tmax of the heart and liver was 20 min. The Tmax of all the components in the lung was 50 min, while the Tmax of the spleen and kidney was from 80 to 100 min, suggesting that 9 bioactive components entered the blood rapidly and then distributed to the heart and liver in large quantities, before entering the lung tissue in large quantities and eventually distributing to the spleen and kidney. The elimination half-life (T1/2) of the majority of 9 bioactive components was less than 1 h, and the MRT of most of them was less than 3 h. Conclusions: S. grosvenorii is a naturally lung-targeted herbal medicine, and the clinical administration ought to be based on pharmacokinetic parameters such as Tmax, Cmax, AUC0 ->infinity, T1/2, and MET0 ->infinity in lung tissue for designing a precise, rigorous, and rational administration plan.

The bicarbonate-formate (HCO3 - - HCO2 -) interconversion provides a promising cycle for a conveniently accessible hydrogen storage system via reversible dehydrogenation and hydrogenation processes. Existing catalytic systems often use organic solvents, tedious optimization as well as manipulation of pH values, solvent, pressure and various additives. Herein, we present an operational, robust, safe and cost-effective catalytic system for hydrogen storage and liberation. We have established a unique catalytic system with two different solid organometallic assemblies (NHC-Ru and NHC-Ir) that facilitate the reversible transformation between sodium formate and bicarbonate in aqueous solutions collaboratively and efficiently. Notably, the NHC-Ru catalyst is privileged for the hydrogenation of sodium bicarbonate, whereas the NHC-Ir component enables the dehydrogenation of sodium formate, all in a single reaction vessel. What sets this system apart is its simplicity. The H2 discharging and recharging is simply regulated by heating the mixture with or without H2 . Remarkably, this process requires no extra additives or supplementary treatments. Moreover, the reversible hydrogen storage system is durable and can be reused for over 30 cycles without a discernible decline in activity and selectivity. The strategic paradigm in this study shows significant practical potential in hydrogen fuel cell applications. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Indolines, a privileged scaffold in natural products and bioactive molecules, hold immense potential in drug discovery and organic synthesis. Herein, we report a photocatalytic dearomatization strategy for the diastereoselective synthesis of unusual cis-2,3-disubstituted acyclic indolines from readily available indoles, aldehydes, and simple feedstocks. This method provides an efficient access to a diverse array of cis-acyclic indolines with high diastereoselectivity, which can be readily converted to their trans-isomers under alkaline conditions. Mechanistic studies reveal the critical role of solvent polarity in modulating isomerization rates, with low-polarity solvents retarding the cis-to-trans transformation. Notably, we uncover the unique photo-activated base properties of TBADT, offering new insights into photocatalytic processes. The biological evaluation demonstrates promising anti-cancer activity of products, underscoring the utility of this approach in medicinal chemistry. This work not only advances the synthesis of cis-indoline-based compounds but also opens new avenues for the development of bioactive molecules and functional materials.

Herein, the structural modification of noscapine via an elegant selenium scanning strategy has been demonstrated, which enables the production of three classes of novel seleno-containing noscapinoids, namely 6', 7', and 9'-seleno-substituted noscapines. Among them, 9'-seleno-substituted noscapines exhibited superior in vitro anti-proliferative activity, and 9'-cycloheptylselenomethyl-noscapine 17a16 with a large hydrophobic cycloheptyl group showed the most potent activity and good selectivity. Unlike most of the reported noscapinoids that induce G2/M phase arrest by targeting microtubules, 17a16 exhibited a distinct ability to induce S-phase arrest and displayed superior potency in inducing apoptosis, which attribute to the activation of two parallel checkpoint pathways orchestrating DNA damage response, including DNA-PKcs-dependent p53 stabilization and ATR-Chk1 axis activation. Dissecting the upstream mechanism revealed that 17a16 targets mitochondria and induces mitochondrial dysfunction. This study elucidates the interplay of mitochondrial stress, DNA damage response, p53 and ATR-Chk1 checkpoint activation in mediating the anticancer effects of 17a16. Furthermore, 17a16 treatment significantly suppressed tumor growth in p53-deficient JeKo-1 subcutaneous xenograft model in vivo, without inducing systemic toxicity. Overall, our findings highlight 17a16 as a promising lead compound in cancer therapy and demonstrate the potential of selenium scanning as a valuable strategy for anticancer drug discovery.

The NADPH oxidase 2 (NOX2) complex is a critical regulator of immune homeostasis. It is utilized by phagocytic leukocytes including neutrophils, monocytes, and macrophages to generate reactive oxygen species (ROS) that drive microbe clearance and modulate inflammatory responses. Within NOX2, the essential scaffold protein p47phox plays a pivotal role in orchestrating enzyme activation and facilitating the assembly and membrane translocation of cytosolic components of the complex. Tight regulation of p47phox activity is crucial, and its disruption is linked to a number of pathological conditions. Conversely, its hyperactivity contributes to oxidative stress, tissue damage, the progression of cardiovascular diseases, neurodegenerative disorders, inflammatory conditions, metabolic syndromes, and cancer. In this review, we detail the structural and functional roles of p47phox, mechanisms of its regulation, and its multifaceted contributions to disease pathogenesis. We explore the latest advances in p47phox-targeted therapeutic strategies, discuss current challenges in the field, highlight p47phox’s potential as a transformative target in redox biology and propose future directions to unlock its clinical utility.