4-Hydroxyphenylpyruvate dioxygenase (HPPD) has become an attractive target for herbicide development owing to the slow development and low risk of resistance to its inhibitors. However, most available HPPD inhibitors exhibit limited crop selectivity and poor efficacy against grasses. Therefore, the exploration of novel molecular scaffolds is of great research value. In this study, we adopted a ring-fusion strategy to enhance π-π stacking interactions and developed a structurally novel pyrazole-4-chloro-benzimidazolin-2-one scaffold. Through systematic structural optimization, compound II-19 showed the strongest enzyme inhibitory activity, with an IC50 of 52 nM, about 6-fold higher potency than the positive control, mesotrione. The crystal structure of AtHPPD-II-19 revealed that the inhibitor engages in characteristic chelation and π-π stacking interactions within the active site, and the 3-NO2-benzyl group contributes additional hydrophobic interactions and a possible weak water-mediated interaction involving Gln293. Additionally, I-5 showed excellent broad-spectrum weed control and good safety toward peanut at 30 g a.i./ha. These results indicate that compound I-5 is a promising candidate for the development of new HPPD inhibitors for weed control in peanut fields.

This highlight discusses the study by Yang et al. (Cell, 2026), which reveals an unexpected function of strigolactone (SL) signaling in rice antiviral immunity. This work shows that SL signaling promotes antiviral RNA interference (RNAi) through the ONAC131-MID1-RDR1/RDR6 pathway. Rice grassy stunt virus (RGSV) suppresses this defense through viral protein P3, which targets SL receptor DWARF14 (D14) at its DWARF3 (D3)-binding interface and stabilizes repressor D53, thereby attenuating RDR1/RDR6 expression and virus-derived small interfering RNA amplification. Structural and genetic analyses identify D102 of D14 as a critical determinant of the P3-D14 interaction but not of SL perception. Precise base editing of D102N generates transgene-free rice lines with enhanced RGSV resistance while maintaining normal growth and yield. This work establishes phytohormone receptors as editable targets for crop protection and provides a promising strategy for engineering durable antiviral resistance in rice.

Solanesyl diphosphate synthase (SPS) is crucial for photosynthesis, as it supplies prenyl precursors for the biosynthesis of the photosynthetic electron carrier, plastoquinone-9 (PQ-9). Fibrillin 5 (FBN5) stimulates SPS catalytic activity through direct binding, which is essential for normal plant growth. However, the molecular mechanism of FBN5-mediated SPS catalytic regulation remains unclear. In Oryza sativa (rice), OsSPS3 is an important plastid-localized SPS isoform involved in PQ-9 formation. The Osfbn5 mutant plants display photodamage with exacerbated PQ-9 deficiency when exposed to high light. Here rice serves as a model organism to study SPS and FBN5. We report the crystal structures of the apo and inhibitor-bound forms of OsSPS3, revealing the alternating catalytic mechanism of the asymmetric OsSPS3 dimer. In addition, we report the cryo-electron microscopy structures of the apo and ligand-bound forms of the OsSPS3-FBN5 complex, showing that OsFBN5 binding triggers an open-to-closed conformational transition of a lid-like capping loop within the inactive monomer of OsSPS3, allowing both monomers of dimeric OsSPS3 to be catalytically active. A comparison of the enzymatic activities of the wild-type OsSPS3 homodimer and a recombinant OsSPS3 heterodimer containing one inactive mutant subunit revealed that OsFBN5 enhances the activity of OsSPS3 by inducing a synchronous catalytic mechanism. This work reveals the dynamic catalytic mechanism of OsSPS3 and provides a structural basis for understanding its function and the FBN5-mediated regulation of the PQ-9 biosynthesis pathway.

Farnesyltransferase (FTase) mediates Ras prenylation, a crucial activation step. Historically, farnesyltransferase inhibitors (FTIs) failed in Ras-driven cancers because of geranylgeranyltransferase I (GGTase I)-mediated alternative prenylation of Ras. Recent advances have revitalized next-generation FTIs, developed via structure-guided design, phenotypic screening, or computational approaches, offering improved selectivity, dual FTase/GGTase I targeting, or enhanced peptidomimetic affinity to overcome resistance. Combinations with targeted agents or immunotherapies exert synergistic antitumor effects. FTIs are also explored for neurodegenerative, infectious, and viral diseases. In this review, we highlight advances in FTIs, their combination strategies and cross-disease potential, justifying why modern FTI approaches succeed where earlier ones faltered.

Triketones are fundamental building blocks in discovering many bioactive compounds due to their unique structural features. With three carbonyl groups and the ability to tautomerize into enol forms, triketones can form hydrogen bond donors and acceptors when binding to receptors and serve as metal chelation function groups. This structural diversity enables triketone compounds to be widely applied in herbicides, fungicides, insecticides, anticancer treatments, and tyrosine metabolism disorders, particularly applications as HPPD (4-hydroxyphenylpyruvate dioxygenase) inhibitors, where their herbicidal activity stems from the disruption of plant photosynthesis processes to effectively control weed growth. Moreover, in materials applications, their excellent reactivity allows for the post-polymerization modification of triketone-modified polymers. To facilitate the discovery of triketone pesticides and drugs, in this review, we summarize the current research progress of triketone compounds, highlighting their potential mechanisms of action and environmental fate. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

4-Hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) is an important target for modern herbicide discovery. To translate HPPD inhibitors into effective herbicide candidates, we developed a metabolism-oriented design strategy to improve the in vivo efficacy of triketone-quinoline HPPD inhibitors. By shielding the metabolic hotspots within the scaffold, we discovered a series of new analogues with broadly improved postemergence herbicidal activity and substantially enhanced inhibition of Arabidopsis thaliana HPPD (AtHPPD). Notably, 9i showed a Ki value of 0.0012 μM toward AtHPPD, outperforming mesotrione by an order of magnitude. 11b not only exhibited excellent weed control at 15.625-250 g ai/ha, but also showed high crop safety to wheat at 250 g ai/ha. Molecular simulations showed that quinoline substitutions could enhance π-π interactions with Phe360 and Phe403, improving bioactivity. Our work establishes a metabolism-guided optimization framework for herbicide discovery and provides a promising wheat-selective herbicide candidate.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is a promising target for new herbicide research. To develop new HPPD-inhibiting herbicides, we used a scaffold-hopping strategy by introducing a quinazolinone ring and combining it with the classic triketone pharmacophore, designing and synthesizing a series of novel HPPD inhibitors with a fused-ring architecture. The results showed that II-series of compounds exhibited excellent inhibitory activity against Arabidopsis thaliana (At) HPPD, with IC50 values 0.5- to 2.5-fold lower than those of mesotrione. Moreover, we obtained the crystal structure of AtHPPD-II-36 complex at a resolution of 1.8 Å. Importantly, II-36 exhibited high safety to wheat and outstanding herbicidal efficacy against Echinochloa crus-galli, Digitaria sanguinalis, and Bromus japonicus at a dosage of 30 g ai/ha. Our study provides a valuable example for designing novel HPPD inhibitors with enhanced herbicidal activity and improved crop selectivity.

Herbicide resistance threatens sustainable weed control and demands new design strategies beyond conventional single-target chemistries. Protoporphyrinogen oxidase (PPO) and solanesyl diphosphate synthase (SPS) are two essential enzymes linked to chlorophyll biosynthesis and plastoquinone production, respectively, making them attractive targets for combinatorial intervention in plants. Here, we report the structure-guided development of a dual-target PPO/SPS inhibitor from the herbicide scaffold aclonifen. Among the synthesized analogs, compound 3q retained potent inhibition of AtSPS1 while exhibiting a ∼60-fold improvement in NtPPO inhibition relative to aclonifen. Differential scanning fluorimetry supported direct engagement of both targets by 3q. A co-crystal structure of the SPS-3q complex revealed binding at the dimer interface and stabilization through π-π interactions with Phe211, whereas molecular dynamics simulation and mutational analysis supported the binding mode of 3q in PPO. In planta, 3q strongly inhibited primary root growth, triggered reactive oxygen species accumulation, and caused characteristic bleaching and burning-curling phenotypes. Notably, 3q remained active against an R128G PPO-resistant Amaranthus retroflexus biotype under greenhouse conditions. Together, these results establish 3q as a dual-target herbicide and provide a proof-of-concept that simultaneous inhibition of PPO and SPS can be exploited to overcome resistance and expand herbicide design strategies.

Neopeltolide, a macrolide natural product of marine origin, was initially isolated from a deep-sea sponge belonging to the Neopeltidae family. This compound has garnered significant attention due to its intriguing structural complexity and remarkable biological potency. Since its discovery, the scientific community has reported over twenty distinct total syntheses, formal syntheses, and fragment syntheses of this natural product, along with developing more than eighty neopeltolide analogues with their corresponding biological evaluations. This comprehensive review systematically examines the biological profile of neopeltolide and elucidates its structure-activity relationships. We provide a detailed overview of the synthetic approaches and biological evaluations of neopeltolide and its structural analogs, with particular emphasis on the synthetic efforts that have contributed to understanding its structure-activity relationship.

Class IIa histone deacetylases (IIa HDACs) have been considered as the key regulators of numerous cellular processes, and related to many diseases included cardiovascular disease, cancer, inflammation, diabetes, neurodegenerative diseases and epigenetic response to drug stimulus. However, the understanding of detailed function of IIa HDACs remain breezing. One reason is that understanding the function not only need detect the expression of IIa HDACs at various condition or stimulus but also determine their distribution, because IIa HDACs can shuttle between nuclear and cytosolic in a phosphorylation-dependent manner and their function was regulated by the shuttling behavior. Hence, we generated a highly specific small-molecule fluorescent probe targeting IIa HDACs (NFP-HDAC). The probe exhibits ultrahigh temporal-spatial resolution and excellent cell penetration capacity, and can accurately monitor the expression, phosphorylation level and distribution of IIa HDACs. This work offers a novel visible tool for the imaging of IIa HDAC related tumor and molecular biology research about IIa HDACs.

The digestive system is one of the most essential systems of multicellular organisms. As an important part of the digestive system, the intestine plays a crucial role in the physiological activities of multicellular organisms. Therefore, intestinal health monitoring technology is vital to human health and animal husbandry. 5-hydroxytryptamine (5-HT) is closely related to many intestinal diseases, including bowel cancer and enteritis, and has great potential as a biomarker of intestinal health status. In this study, a fluorescent probe FHT was discovered. The probe has high selectivity and sensitivity to 5-HT (LOD = 0.22 μM). More importantly, imaging experiments in zebrafish and mice showed that 5-HT content was positively correlated with intestinal health status. Based on the probe, we developed a general visual intestinal health examination method, which provides a new tool for intestinal health monitoring.

Oncolytic virus therapy (OVT) represents a promising frontier in cancer treatment. Despite its efficacy in clinical trials, variability in patient response, particularly resistance development, highlights the need for tailored therapeutic strategies. The Inositol Hexakisphosphate Kinase 2 (IP6K2) gene knock out was carried by CRISPR/Cas9 system. The evaluation of biomarkers of apoptosis and relevant pathways was conducted to be assessed. Attachment assay was conducted to verify the binding ability of virus to the host cells. Cell proliferation and apoptosis was assessed. Subcutaneous xenograft model was used to evaluate IP6K2 knock out influence in vivo. cBioPortal and TCGA database were applied to analyze genomic alterations in pan-cancer. IP6K2 was essential for effective Herpes Simplex Virus Type1 (HSV-1) replication and subsequent cell apoptosis, acting through the tumor Protein p53 (p53) and Cyclin-Dependent Kinase Inhibitor 1 A (p21) signaling axis. The tumor model demonstrated that tumors lacking IP6K2 exhibited resistance to HSV-1 oncolysis, resulting in diminished therapeutic outcomes. Analysis of cBioPortal and TCGA databases corroborated the potential resistance stemming from IP6K2 mutations across various cancer types, underscoring the necessity for pre-treatment IP6K2 status assessment. This study underscores the role of IP6K2 as potential markers of resistance, which opens avenues for precision medicine approaches in OVT. First reported that Inositol Hexakisphosphate Kinase 2 (IP6K2) is crucial for effective HSV-1 oncolytic virus therapy. CRISPR/Cas9-mediated knockout of IP6K2 resulted in decreased virus replication and apoptosis in cancer cells. Tumors lacking IP6K2 in vivo showed significant resistance to HSV-1 oncolysis, leading to reduced therapeutic efficacy. The p53-p21 signaling axis mediates the effects of IP6K2 on HSV-1 therapy efficacy. cBioPortal and TCGA database analyses confirmed that IP6K2 mutations are associated with resistance to oncolytic virus therapy across multiple cancer types. Highlighted the importance of assessing IP6K2 status prior to treatment to optimize oncolytic virus therapy for individual patients.

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) has long been recognized as a validated target in herbicide development. In this research, through structural analysis, we devised an Active Fragment Exchange and Link (AFEL) methodology to engineer a new category of N-phenyltriazinone derivatives. These compounds feature ether-connected oxadiazole moieties and serve as potent inhibitors of Nicotiana tabacum PPO (NtPPO). Following systematic structure-activity relationship (SAR) optimization, 34 novel compounds were identified. These compounds exhibit nanomolar Ki values against NtPPO and show promising herbicidal activity, with some compounds demonstrating lower Ki values compared to saflufenacil. Greenhouse herbicidal activity assays revealed that compound Iq exhibited the highest efficacy, achieving 100% inhibition against tested broadleaf weeds at 37.5 g a.i./ha, comparable to saflufenacil. Compound Iq exhibited better crop safety for maize at 150 g a.i./ha relative to saflufenacil. Molecular docking simulations revealed that the oxadiazole ring in compound Iq forms two hydrogen bonds with the Arg98 residue of NtPPO. These findings suggest that compound Iq has the potential to be a novel PPO inhibitor for managing agricultural weeds.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is a critical enzyme for green herbicide discovery. This study aimed to develop new HPPD inhibitors for the efficient control of Echinochloa crus-galli in rice fields. A series of 41 triketone derivatives were designed and synthesized using structure-based and proherbicide strategies. The herbicidal activity of the newly synthesized compounds was evaluated against common weeds in rice fields, including E. crus-galli and Leptochloa chinensis. Among them, 2-(2-chloro-4-(methylsulfonyl)-3-((2,2,2-trifluoroethoxy)methyl)benzoyl)-3-((5-methoxy-1H-benzo[d]imidazol-2-yl)thio)cyclohex-2-en-1-one, compound IIy, showing high efficiency against E. crus-galli and L. chinensis, including the resistant biotypes at dosages as low as 19.62-33.26 g of ai/ha, which were significantly more active than that of bicyclopyrone. The density functional theory calculations and metabolism studies revealed the action mechanisms of IIy. The field trials showed that IIy could effectively control the weeds in rice fields at 90-150 g of ai/ha by postemergence application. Our findings suggested the great potential of IIy to be developed as a highly effective herbicide for weed management in paddy fields.

Tetracycline hydrochloride (TCH) abuse results in drug residues that pose significant risks to both human health and ecosystems while also obstructing sustainable development. In this work, we developed a ratiometric fluorescence sensor that combined nitrogen and sulfur co-doped carbon dots (N, S-CDs) with a zinc-based metalorganic framework (Zn MOF). When TCH was added, fluorescence sensing tests showed that the inner filter effect (IFE) caused a blue fluorescence quenching at 416 nm. At 515 nm, the aggregation-induced emission effect (AIE) produced a new green fluorescent signal. The detection method showed the benefits of a quick response time (1 min) and a low detection limit (8.6 nM). Additionally, a smartphone-based assisted agar slice detection platform was developed for the visual and quantitative detection of TCH. The device was a cost-effective, portable sensing instrument with a detection limit of 79 nM, offering high sensitivity and user-friendly operation. Most significantly, the agar slice platform has improved the use of portable quantitative sensing devices in the sensing field by demonstrating excellent utility and dependability in real sample detection of TCH.

Chemodynamic therapy (CDT) is an emerging treatment strategy that kills tumor cells by generating hydroxyl radicals (·OH) via the activation of Fenton/Fenton-like reactions within the tumor microenvironment (TME). Although CDT overcomes drug resistance issues and has minimal side effects, it still faces multiple challenges including low endogenous hydrogen peroxide (H2O2) levels, inadequate catalytic efficiency, and targeting issues. To overcome these limitations, a novel precision-targeted responsive molecularly imprinted nanozyme (GZMIP) was developed. Using zeolitic imidazolate framework-8 (ZIF-8)-coated glucose oxidase (GOx) as a carrier (GZ) and the epitope of lactate transporter (MCT4) as the template, an imprinted layer was prepared on the GZ surface via radical polymerization reactions, followed by elution to obtain GZMIP. GZMIP targeted tumor cells with overexpressed MCT4. Upon entering cells, GZMIP occurred responsive cleavage in the acidic environment and GSH overexpressed TME, releasing GOx and copper(II) acrylate (CuA) monomers from the imprinted layer. GOx catalyzed intracellular glucose (Glu) to generate H2O2, while GSH reduced CuA to Cu+. The subsequent cascade reaction between Cu+ and H2O2 generated highly toxic ·OH, inducing cell death. Both in vitro and in vivo experiments demonstrated that GZMIP effectively inhibited tumor cell proliferation, showed a 75 ± 5 % growth inhibition rate in tumor-bearing mouse models, and exhibited excellent biocompatibility. This study innovatively integrated molecular imprinted polymers with nanozyme technology to establish a Fenton-like cascade catalytic system, simultaneously achieving precise delivery and controlled release of catalytic components. This approach significantly improving tumor targeting and therapeutic efficacy, providing a promising strategy for enhanced CDT.

Recent advances in target-based pesticide design have identified numerous novel candidate targets, although their agrochemical potential requires rigorous validation. Fluorescent probes serve as critical tools for tracing molecular interactions and elucidating the target functionality. Herein, we developed a complementary fluorescent probe pair (HDP1 and HDP2) to systematically reveal the challenge of targeting histidinol dehydrogenase (HDH) as an agrochemical target. HDP1 exhibits an outstanding detection limit (0.17 μg/mL), while HDP2 demonstrates excellent imaging capabilities in vivo. HDP1 was used to probe the interactions between inhibitors and substrates with HDH, confirming that HOL, the natural substrate of HDH, exhibits a strong and competitive affinity for HDH similar to that of HDH inhibitors (HDHIs). HDP2 was employed to image HDH in Arabidopsis thaliana, Escherichia coli, and Saccharomyces cerevisiae during treatment with HDHIs or under other stresses to show the change of the flux through the histidine biosynthesis pathway. The results indicate that HDHIs, non-HDH-targeting pesticides, and abiotic stresses can all affect His biosynthesis in plants, bacteria, and fungi. The results also show that various stresses can influence the histidine biosynthesis pathway through the regulation of the pentose phosphate pathway and inhibition of the expression of ATP-phosphoribosyltransferase. It can be concluded that the development of competitive inhibitors for HDH that can compete with HOL and show activity in vivo is a significant challenge. The sensitivity of the His biosynthesis pathway to other stresses complicates the picture and, under different conditions, may provide a positive or negative factor for HDH inhibition by synthetic ligands.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is recognized as one of the most promising herbicide targets for sustainable weed control in modern agricultural practices. To address agricultural demands, we designed and synthesized a novel series of triketone-quinoxalin-2-ones as potent HPPD inhibitors. In vitro evaluation revealed that the newly synthesized compounds demonstrated remarkable Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity. Significantly, compound 23, 3-(4-chloro-2-fluorophenyl)-6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethylquinoxalin-2(1H)-one, showed the strongest AtHPPD inhibition with an IC50 value of 0.034 μM, 10-fold more potent than mesotrione (IC50 = 0.350 μM). Furthermore, the postemergence herbicidal activity evaluation showed that compound 35 exhibited 100% inhibition of Digitaria sanguinalis, Amaranthus retroflexus, Chenopodium serotinum, and Abutilon theophrasti at 150 g ai/ha, and 90% inhibition of Setaria viridis, showing enhanced activity compared to mesotrione. The crystal structure of the AtHPPD-35 complex demonstrated that compound 35 engaged in a key bidentate chelating interaction with the metal ion in the catalytic active site and a π-π interaction with Phe381 and Phe424. Moreover, 35 established hydrophobic interactions with Leu427, Leu368, and Met335. These results indicate that the triketone-quinoxalin-2-one hybrid is a promising scaffold and 35 can be considered a viable lead compound for the development of HPPD inhibitors.

Large language models (LLMs), especially Explicit Long Chain-of-Thought (CoT) reasoning models like DeepSeek-R1 and QWQ, have demonstrated powerful reasoning capabilities, achieving impressive performance in commonsense reasoning and mathematical inference. Despite their effectiveness, Long-CoT reasoning models are often criticized for their limited ability and low efficiency in knowledge-intensive domains such as molecule discovery. Success in this field requires a precise understanding of domain knowledge, including molecular structures and chemical principles, which is challenging due to the inherent complexity of molecular data and the scarcity of high-quality expert annotations. To bridge this gap, we introduce Mol-R1, a novel framework designed to improve explainability and reasoning performance of R1-like Explicit Long-CoT reasoning LLMs in text-based molecule generation. Our approach begins with a high-quality reasoning dataset curated through Prior Regulation via In-context Distillation (PRID), a dedicated distillation strategy to effectively generate paired reasoning traces guided by prior regulations. Building upon this, we introduce MoIA, Molecular Iterative Adaptation, a sophisticated training strategy that iteratively combines Supervised Fine-tuning (SFT) with Reinforced Policy Optimization (RPO), tailored to boost the reasoning performance of R1-like reasoning models for molecule discovery. Finally, we examine the performance of Mol-R1 in the text-based molecule reasoning generation task, showing superior performance against existing baselines.