IntroductionAs a unique collagen-activated receptor tyrosine kinase, discoidin domain receptor 1 (DDR1) mediates signaling essential for cell proliferation, survival, adhesion, and matrix remodeling. Conversely, its dysregulation is implicated in cancer, tissue fibrosis, atherosclerosis, and other inflammatory diseases. Emerging research reveals that the non-catalytic functions of DDR1 are critically involved in tumor progression, metastasis, and immune exclusion. Selectively inhibiting the catalytic and/or non-catalytic functions of DDR1 presents a promising therapeutic strategy for various diseases.Areas coveredThis article summarizes current progress on the development of inhibitors, degraders and biomolecules targeting DDR1 and their potential therapeutic application during the period from 2020 to 2025.Expert opinionSignificant efforts have been made to develop small-molecule DDR1 kinase inhibitors, yet achieving high selectivity remains a challenge. Degraders have been developed to inhibit both its catalytic and noncatalytic functions. Although these molecules offer conceptual advantages over traditional kinase inhibitors, they suffer from suboptimal pharmacokinetic properties. Alternatively, biologics such as antibodies and peptides can block the DDR1-collagen interaction, specifically inhibiting non-catalytic signaling, and one antibody is currently under clinical evaluation. Moving forward, the development of highly selective inhibitors and improvement of pharmacokinetic profiles for degraders will be pivotal for translating DDR1 targeting into viable therapies.

Generative AI algorithms such as the transformer and diffusion models have greatly empowered de novo design of proteins capable of specifically interacting with designated structural sites on another protein. Most of these design methods employ a top-down approach, in which an overall protein shape is generated by an AI model to pack against a given structural site, followed by sequence design to optimize the interaction. Despite being trained on limited protein complex structures available in the database, the top-down approach has yielded encouraging results. Here, we propose a bottom-up approach that generates atom clusters for optimal packing against a specified structured region for informing the design of protein-protein interactions. To this end, we trained a masked discrete diffusion model, named Void-X, that uses the diffusion transformer to learn atomic-level interactions and fill atomic voids in protein interaction interfaces. Void-X was trained using 8.7 million spherical clusters of atoms from experimental structures in the Protein Data Bank. In each cluster, similar to 70% of the atoms are used as context (or prompt), and similar to 30% are masked for information recovery (or answer). By training the model with 172 million parameters, Void-X achieves an overall accuracy of 78.3% and 68.2% for intra- and interchain spherical clusters, respectively. Furthermore, we find that information entropy is a reliable indicator of the prediction accuracy for Void-X. This level of performance allows de novo generation of molecular interactions at the atomic level, offering an alternative approach of protein design complementary to the existing ones.

Ru(I) radicals with a 4d 7 electronic configuration are sought after for their unique electronic structure and synthetic utility in chemical transformations. However, due to their high reactivity, ligand scaffolds effecting the stabilization of Ru(I) species are exceedingly rare. In this study, we present readily accessible, persistent Ru(I) radicals supported by N-heterocyclic carbenes (NHCs) and p-cymene, [RuCl(NHC)(eta 6-p-cymene)]. These halide complexes are easily prepared via single-electron reduction of their Ru(II) dichloride precursors. Integrated single-crystal X-ray diffraction, EPR spectroscopy, magnetic measurements, and DFT studies establish an S = 1/2 ground state with spin density primarily localized on ruthenium. Frontier molecular orbital analysis indicates that the stabilization of these Ru(I) radicals originates from the synergistic interplay of the strong sigma-donation from the NHC ligand and delta-acceptance of the arene ligand. Accordingly, voltammetry study showes a reversible one-electron oxidation at relatively high potential (E 1/2 = -0.32 V vs. SCE) and an irreversible one-electron reduction at very low potential (E p = -2.17 V vs. SCE). Furthermore, the chloride ligand in these Ru(I) complexes allows chloride-to-phosphine exchange reaction as demonstrated by the preparation of the cationic Ru(I) complex [Ru(PMe3)(IMes)(eta 6-p-cymene)][BPh4] from the reaction of [RuCl(IMes)(eta 6-p-cymene)] with PMe3 and NaBPh4, underscoring their utility as tunable precursors for catalysis.

Electrochemical transformations of epoxides have emerged as a useful platform for alcohol synthesis, and their reactivity and selectivity are strongly dictated by the substitutions of the epoxides. Incorporation of an alkynyl substituent into the epoxide framework offers a promising yet unexplored avenue toward highly functionalized different alcohol derivatives posing formidable challenges in selectivity control. Here, we report an earth-abundant metal of nickel-catalyzed cross-electrophile coupling between readily available alkynyl epoxides and aryl/alkenyl halides, enabling the highly selective synthesis of allenols under mild electrochemical conditions. This protocol exhibits a broad substrate scope, preferential C-O bond activation over C-X bonds, and a decent chemoselectivity for C-I activation over the C-Br bond, while tolerating a wide array of synthetically valuable functional groups, such as free hydroxyl, ketone, carboxylate, methoxy, TBS ether, N-Boc, highly strained cyclopropyl, C & boxH;C bonds, C-TMS, C-F bonds, C-Cl bonds, C-Br bonds, and even C-B bonds. Moreover, this methodology may also apply to the synthesis of allenols bearing pharmaceutical and biologically active moieties, and the downstream derivatizations of allenol products have also been realized, offering a modular platform for the synthesis of diversified functional structures.

Terpenoids are a large and structurally diverse family of natural products with significant pharmacological activities. A key structural feature found in many of these molecules-including certain Schisandra nortriterpenoids and limonoids-is a unique tetrahydrofuran-lactone-fused motif. Despite its prevalence, a general and efficient method for constructing this framework has remained elusive. Inspired by the biosynthetic pathway proposed for Schisandra nortriterpenoids, our group has developed a bioinspired skeletal reorganization strategy that leverages a biomimetic transesterification/oxa-Michael addition (TOMA) cascade to efficiently build the complex fused-ring systems from readily prepared precursors. The utility of this TOMA cascade has been demonstrated through the successful synthesis of three terpenoid natural products: propindilactone G, rubriflordilactone B, and deoxylimonin.

The solvation structure of Li+ critically governs charge-transfer kinetics and interfacial chemistry in lithium metal batteries (LMBs), yet achieving desired modulation is highly challenging due to the intertwined Li+-anion and solvent interactions. This complexity becomes particularly critical under fast-charging conditions, where sluggish Li+ desolvation and unstable interphases severely limit electrochemical kinetics. Here, we report a solvent-type and molecularly engineered lithium organofluorinated aluminate salt (LiFA), with a polyether chain adjacent to the aluminate center, allowing the salt to encapsulate Li+ into its solvation domain, while the electron-deficient aluminate core and bulky fluorinated pendants achieve delocalization of charge and promote Li+ dissociation. In-depth experimental and molecular dynamics analyses reveal that such salt design could enable dynamic reconfiguration of Li+ solvation structures and balance between contact ion pairs and solvent-separated ion pairs, substantially accelerating charge-transfer and stabilizing the interfaces. This solvent-type salt strategy offers a dynamic solvation regulation approach to reconfigure the Li+-anion coordination environment and synergistically enhance desolvation kinetics from interfacial stability, shedding light on electrolyte discovery toward fast-charging and durable LMBs.

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Here, we report the asymmetric total syntheses of two C11-oxygenated napelline-type alkaloids, including (+)-Pendulumine I and (+)-Aconicarmichinium C, which hinge on the strategic design of a regioselective and enantiospecific trapping of a highly reactive [3.2.1]-bridgehead enone intermediate via a kinetic-resolution-enabled intermolecular Diels-Alder reaction. Combined experimental and computational studies revealed that the developed bridgehead-enone-mediated [4 + 2]-cycloaddition could proceed in a concerted and enantioselective process, wherein the observed excellent kinetic-resolution outcome was jointly governed by the distinct steric repulsion and the favorable secondary orbital interaction (endo-type) both between a tailored chiral diene featuring a stereospecific oxygenated substituent at C1 and in situ generated racemic bridgehead enones. Coupled with a transannular intramolecular Mannich reaction to rapidly assemble the cage-like hexacyclic framework and a sequence of organized oxidation-state manipulations to precisely install oxygenated substitutions in the core skeleton, our strategy would streamline the synthetic design of ent-kaurenoid alkaloids and pave the way for their modular syntheses, as well as highlight the powerful utility of bridgehead-enone intermediates in the stereoselective construction of bridged polycyclic systems.

An efficient Pd-catalyzed C-S coupling strategy for the synthesis of tetrasubstituted allenyl sulfones has been developed. Excess sulfinate uniquely acts as both coupling partner and isomerization promoter, driving the in situ generated propargyl sulfone to allenyl sulfone conversion with a high regioselectivity and a broad substrate scope.

The halogenated natural product naphthacemycin was isolated from Streptomyces sp. N12W1565 strain associated with the stems of the traditional Chinese medicinal herb Senecio scandens Buch.-Ham. Ex D. Don. Previous studies have established that polychlorination of this metabolite was catalyzed by the multi-site halogenase NatC encoded within the naphthacemycin biosynthetic gene cluster, suggesting that modulation of halide species in the culture medium can enable the generation of diverse halogenated analogues. In this study, brominated naphthacemycins were produced by optimizing the fermentation conditions of this strain. Three novel monobrominated naphthacemycins were successfully characterized by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance (NMR) spectroscopy, among which naphthacemycin BB1 (5) and naphthacemycin BB3 (7) exhibited significantly enhanced antibacterial activity compared to the non-brominated naphthacemycin B-2 (1).

Biocatalysis has emerged as an essential green manufacturing approach, enabling sustainable and efficient synthesis across the pharmaceutical, agricultural, and food industries. Beyond its fundamental significance in elucidating molecular evolution, ancestral sequence reconstruction (ASR) has also proven to be a powerful technology for engineering enzymes with enhanced properties or novel functionalities. ASR infers the sequences of ancestors by comparing the sequences of extant (current) enzymes. This approach has proven highly versatile, not only facilitating the generation of robust enzymes with increased activity and/or promiscuity, improved stability, and selectivity but also offering a unique framework for investigating fundamental mechanisms and biochemical principles that are difficult to address using contemporary enzymes alone. This review highlights the advances in ASR over the past three years across diverse applications, including regulation of enzyme function and selectivity, investigation of functional divergence mechanisms, enhancement of thermostability and catalytic activity, and expansion of substrate scope. We anticipate that ASR will play an increasingly central role in advancing biocatalytic applications. Indeed, the field of enzyme engineering is currently undergoing a trans-formative phase, driven by the synergistic integration of computational evolutionary tools and experimental validation, which continues to unlock the functional potential of biocatalysts.

The integration of fundamental redox and Lewis acid manifolds in catalysis is a pivotal goal in synthetic chemistry, promising to unlock unconventional reactivity. It typically requires two distinct metals as a single metal usually performs only one role. Therefore, achieving both functions from a single metal precursor represents an attractive, yet challenging, goal. Herein, we address this challenge through the rational design of a multifunctional ligand that features complementary coordination units for differentiating two identical metals to perform distinct functions. This ligand enables the assembly of a dinuclear Ni catalyst, wherein one Ni center acts as a Lewis acid, while the second one operates as a redox-active site. This cooperative system achieves an enantioselective hydroalkoxylation of enamides with alcohols, delivering a broad range of valuable acyclic N,O-acetals in high yields and enantioselectivities (up to 98% ee). This work opens a new avenue for the design of advanced catalytic systems.

Organic long-persistent luminescence (OLPL) generally involves charge separation and subsequent retard charge recombination processes. A comprehensive understanding of how trap states regulate the charge recombination process is therefore crucial for the rational design of high-performance OLPL materials. Herein, a donorsensitizer-acceptor strategy is employed to construct a series of ternary OLPL systems, in which TMB (N,N,N ', N '-tetramethylbenzidine) derivatives with systematically tuned highest occupied molecular orbital (HOMO) levels are selected as electron donors. The influence of trap properties on the OLPL performance has been investigated in a systematic manner. By correlating experimental results with theoretical calculations, we demonstrate that OLPL performance is significantly enhanced when the TMB derivatives exhibit a moderate trap depth together with high radical cation stability. These findings establish a clear structure-trap state-performance relationship and provide a rational design principle for high-performance OLPL materials, highlighting their potential for applications in displays and biological imaging.

Diabetic chronic nonhealing wounds are characterized by persistent inflammation, oxidative stress, and impaired tissue regeneration, which are closely associated with receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-mediated programmed cell death. Although RIPK1 kinase represents a promising therapeutic target, its role in diabetic wound healing and effective local delivery strategies remain largely unexplored. Here, we report a local therapeutic system for diabetic wound healing, RIPK1i@PTM/TA, based on a pH/glucose dual-responsive hydrogel biointerface rationally designed to adapt to the pathological wound microenvironment. The hydrogel is constructed from a poly(acrylic acid)-terminal-olefin polyethylene glycol ether-phenylboronic acid copolymer (PTM) and dynamically crosslinked with tannic acid (TA), endowing the network with microenvironmentsensitive structural modulation, tissue adhesion, and antibacterial functionality. RIPK1 inhibitor is stably immobilized within the reversible crosslinked matrix, enabling localized, on-demand, and sustained drug release at the wound-material interface in response to acidic pH and elevated glucose levels. Functionally, RIP-K1i@PTM/TA enhanced fibroblast activity in vitro, and in diabetic chronic wound mouse models effectively suppressed RIPK1-dependent cell death, alleviated inflammation and oxidative stress, and promoted angiogenesis, ultimately accelerating wound closure and structural reconstruction. Collectively, this study demonstrates an effective microenvironment-responsive hydrogel for topical drug delivery in refractory diabetic wounds.

The development of non-conjugated luminescent systems has innovated the traditional design strategy of through-bond conjugation (TBC) and inspired a deeper understanding on molecular photophysics. However, a challenge encountered by these non-conjugated structures is that the fluorescence of pure hydrocarbon systems is largely confined to the blue region (similar to 470 nm), raising the question of whether this is a fundamental limitation. Herein, we break this barrier by constructing a library of over 50 non-conjugated arylated alkenes via binuclear nickel-catalyzed hydroarylation of allenes. It is disclosed that synergistic multiple through-space interactions (TSIs) including molecular twisting-tuned intramolecular TSIs combined with intermolecular TSIs mediated by the double bonds of styrene units are critical for achieving the ultralong-wavelength aggregation-induced emission of these non-conjugated structures. This enables tunable light emission from blue to yellow, orange and, remarkably, even to single-compound-based warm white light. Furthermore, strategic substitution extends the fluorescence into the deep-red region, with a tail reaching 900 nm. This work demonstrates that non-conjugated pure hydrocarbons can achieve a broad spectrum of colors, fundamentally advancing the understanding of the luminescence phenomenon of non-conjugated systems and providing a novel design strategy for luminescent materials beyond the traditional TBC paradigm. Breaking the blue limit of non-conjugated hydrocarbons: via through-space interaction, scientists have pushed pure hydrocarbon fluorescence from blue to deep-red, unlocking warm white light from a single molecule.

beta-Hydroxy-amino acids are key structural motifs of many bioactive natural products, but enzymatic beta-hydroxylation of an aromatic amino acid appears to be uncommon. In known cases, this reaction typically occurs on a residue residing in a peptide scaffold or tethered on a carrier protein via a thioester linkage. EcdG, an alpha-ketoglutarate/Fe(II)-dependent dioxygenase involved in the biosynthesis of echinocandins, is an exception, catalyzing the stereoselective beta-hydroxylation of a free l-homotyrosine amino acid. Here, we report a comprehensive structural and mechanistic study of EcdG and use knowledge gained from this study for functional modulation of the homologous protein GloM. High-resolution crystal structures of EcdG in complex with alpha-ketoglutarate and l-homotyrosine were determined. With the association of site-directed mutagenesis, the molecular basis for substrate recognition and the regio- and stereoselectivity of EcdG was revealed and then used to guide the engineering of GloM. The substrate specificity and oxidation capability of this homologous protein were altered, enabling selective transformation of the unnatural substrate l-homophenylalanine to either a beta-hydroxyl product or a gamma-keto product. This work provides mechanistic insights into a type of uncommon beta-hydroxylase and expands the enzymatic toolbox for selective oxidative functionalization of a free aromatic amino acid.

Background Depression is a common and early non-motor symptom of Parkinson's disease (PD) with significant sexual dimorphism, yet its underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the sex-specific plasma proteomic profiles of depression in patients with PD (DPD) and to investigate the role of complement-mediated synaptic pruning in its pathophysiology. Methods Plasma proteomic analysis was performed on data from the Parkinson's Progression Markers Initiative (PPMI) and an independent validation cohort, stratified by sex. Functional enrichment analyses identified dysregulated pathways. A chronic MPTP/probenecid-induced mouse model of PD was used to validate findings. Behavioural tests assessed motor and depressive-like phenotypes. Proteomic, biochemical, and imaging techniques were used to evaluate protein expression, synapse density, and microglial phagocytosis. The therapeutic mechanism of Botulinum Neurotoxin A (BoNT/A) on DPD was investigated in wild-type, C3-/-and C3aR-/- mice and in microglial cultures. Findings Proteomic profiling revealed both conserved complement-driven immune dysfunction and profound sex-divergent molecular perturbations underlying PD and DPD. Complement and coagulation cascades were consistently upregulated in both sexes. In MPTP-treated male and female mice, hippocampal complement components (C1Q, C3, C3aR) and downstream signalling (p-STAT3, p-P65) were elevated, accompanied by microglial synapse phagocytosis and depressive-like behaviours. Genetic deletion of C3 rescued both MPTPinduced motor and depressive-like behavioural deficits and prevented hippocampal synaptic loss associated with microglial synaptic engulfment. BoNT/A treatment alleviated depressive-like behaviours and reduced microglial synaptic engulfment in an MPTP model; these therapeutic effects were abolished in C3-/- and C3aR-/- mice. Single-cell RNA sequencing and in vitro phagocytosis assay confirmed that BoNT/A modulated phagocytosisrelated microglial subclusters. Interpretation DPD exhibits distinct sex-specific immune signatures, with convergent complement pathway activation driving microglial synaptic pruning and depressive symptoms. The antidepressant effect of BoNT/A is mediated through inhibition of the C3-C3aR signalling axis. These findings highlight the potential for sex-stratified diagnostics and complement-targeted therapies for depression in patients with PD. A key limitation is that our clinical analyses were constrained by limited validation cohort sizes, and mechanistic studies were limited to male mice, which may restrict the generalisability of our findings to female populations. Copyright (c) 2026 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).