Acute kidney injury (AKI) is a heterogeneous syndrome with limited treatments, underscoring the need for new therapies. The natural glycoside kinsenoside is a promising candidate owing to its anti-inflammatory and antioxidant properties. We synthesized a series of kinsenoside derivatives and identified K30 as the most effective nephroprotective compound. In murine models of cisplatin-, folic acid-, and ischemia-reperfusion-induced AKI, K30 significantly preserved renal function, attenuated inflammation and oxidative stress, ameliorated mitochondrial dysfunction, and showed no evident systemic toxicity. Cellular thermal shift assay combined with mass spectrometry identified mammalian STE20-like kinase 1 (MST1) as the direct target of K30, which was further validated by drug affinity responsive target stability assays, molecular docking, surface plasmon resonance and in vitro kinase activity assays. The renoprotective effect of K30 was abolished in MST1-knockdown cells and restored upon MST1 re-expression, and its efficacy was comparable to two established MST1 inhibitors. Mechanistically, K30 exerts its renoprotective effect by directly targeting and inhibiting MST1, thus suppressing the downstream JNK–Drp1 signaling axis, which in turn ameliorates pathological mitochondrial fission. These results demonstrate that K30 is an effective MST1-targeting compound capable of maintaining mitochondrial homeostasis, highlighting its potential as a novel therapeutic agent for AKI.

Glioblastoma multiforme (GBM) is an aggressive, therapy-resistant brain tumor with limited treatment options. Epidermal growth factor receptor (EGFR) drives GBM pathogenesis. Here, we investigate ZYH005 (Z5), a brain-penetrant DNA intercalator with low systemic toxicity, as a novel therapeutic agent. Z5 potently inhibits the proliferation of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) in vitro and suppresses tumor growth in orthotopic GSCs-derived mouse models, significantly prolonging survival without apparent toxicity. Mechanistically, Z5 exerts potent anti-GBM activity through a dual mechanism: DNA intercalation-induced damage and targeted inhibition of EGFR. By specifically inhibiting EGFR at E762, Z5 not only enhances DNA damage by suppressing the DNA damage response in the nucleus but also disrupts the interaction between nuclear EGFR and WEE1, leading to impaired WEE1/CDC2 signaling and G2/M checkpoint failure. Extranuclearly, Z5 further enhances its anti-GBM efficacy by inhibiting the canonical EGFR downstream pathways, mTOR, and ERK. These combined actions lead to cell cycle arrest and mitotic catastrophe. Our findings establish Z5 as a promising clinical candidate for classical GBM, employing a unique dual mechanism that overcomes EGFR-targeted and DNA-damaging therapy limitations by synergistically targeting DNA and EGFR with high efficacy, advancing understanding of EGFR-WEE1 biology, and supporting clinical development.

Based on glutarimide's excellent phamaceutical bioactivities, herein, we developed a Brønsted acid-mediated cationic cyclization reaction of 1,6-enynes with electron-deficient alkyne as terminator. And the substrates can be easily transformed into diversified methylene glutarimides with tetrasubstituted alkenes in moderate to excellent yields. Furthermore, nucleophile scope can be diversified to include not only halides and O-nucleophiles, but also C-nucleophiles and S-nucleophiles. Moreover, this protocol demonstrates operational simplicity, mild reaction conditions, broad substrate scope, and gram-scale synthesis capability.

Background: Glioblastoma (GBM) is a highly aggressive malignancy with limited therapeutic option. EGFR and WEE1 play specific roles in the occurrence and development of GBM and are potential therapeutic targets for it. ZYH005 (Z5) is a DNA intercalator with low systemic toxicity and enhanced blood-brain barrier penetration, its therapeutic efficacy and underlying mechanisms in GBM are worth further exploration. Methods: The antitumor efficacy of Z5 was determined with GBM cell lines and patient-derived glioblastoma stem cells (GSCs) in vitro and in vivo through cell proliferation, colony formation and western blots assays. The targets of Z5 and related mechanisms were validated using CMap, DNA microarrays and surface plasmon resonance (SPR). Results: Z5 demonstrated robust anti-proliferative activity against both conventional GBM cell lines and patient-derived glioblastoma stem cells (GSCs), while significantly suppressing orthotopic tumor growth and prolonging survival in murine models. Mechanistic studies revealed a dual mechanism of action: Z5 directly induces persistent DNA damage and inhibits DNA repair pathways, while simultaneously binding to EGFR's Glu762 residue to disrupt its interaction with WEE1. This interference blocks WEE1 phosphorylation at Ser642, abrogating G2/M checkpoint activation and triggering mitotic catastrophe in cells. Conclusions: These results clearly demonstrate the dual functionality of Z5, which serves as both a DNA intercalator and an EGFR inhibitor. In GBM cells, Z5 effectively induces mitotic catastrophe, and in GSCs-based models, it exhibits remarkable anti - tumor activity. Consequently, Z5 stands out as a highly promising candidate for the development of innovative GBM treatments. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was financially supported by the by the National Natural Science Foundation of China [grant number 82073886], the Program for Medical Youth Talent of Hubei Province (2024-2027), Hubei Provincial Administration of Traditional Chinese Medicine Research Fund [grant number ZY2023M063], the National Key R&D Program of China [grant number 2021YFA0910500] and National Natural Science Foundation of China [grant number 82473132 and 82072805]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: GSC cells were obtained from glioma patients who underwent surgery at the Department of Neurosurgery of Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology. All participants provided written informed consent and the study was approved by the Ethics Committee of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology (Serial number: 2021-lEC-A244). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This study did not generate new regents or original code. All data generated or analyzed during this study are included in this article and its supplementary information files. Microarray data can be accessed through the following link: https://ngdc.cncb.ac.cn/omix/preview/BlYvj2iS.

Meroaspochalasins (mAPOs) are a group of intricate heteromers comprising two distinct subunits, dienophile aspochalasin, and diene isobenzofuran, of which the biosynthetic mechanism is of great interest yet unrevealed. In this study, two independent biosynthetic gene clusters (BGCs), flas and epi, being responsible for the biosynthesis of aspochalasin B (7) and pre-diene hemiacetal 21 (or 26), respectively, were identified in the filamentous fungus Aspergillus flavipes. In vivo and in vitro studies proved that a flavin adenine dinucleotide (FAD)-dependent oxidase FlasF in the flas cluster catalyzes the crucial oxidation to generate diverse aspochalasin monomers, particularly the dienophile 7. Interactive reduction catalyzed by the short-chain alcohol dehydrogenase/reductase (SDR) FlasG and endogenous NADPH further increases the complexity of this anabolic network. The cytochrome P450 enzyme EpiC and SDR enzyme EpiD in the epi cluster collaboratively catalyze the formation of pre-diene 21 (or 26), which can spontaneously dehydrate to yield a diene, leading to the nonenzymatic cascade of [4π + 2π] Diels-Alder and formal [5π + 2π] cycloaddition reaction to generate mAPO dimers and trimer progressively. Moreover, the FAD-dependent oxidase EpiG catalyzes the hydroxylation at the C3 position of the diene as a critical step in the formation of mAPO trimers.

Acute liver injury (ALI), primarily induced by drugs and toxins, is characterized by rapid progression and high mortality. The lack of effective therapeutic agents presents a serious clinical challenge, underscoring the urgent need for novel drug development. Herein, we report two novel kinsenoside (KD) derivatives, KCM and KCF, synthesized via a two-step chemical strategy, which exhibit potent hepatoprotective effects in acetaminophen (APAP)- and thioacetamide (TAA)-induced ALI mouse models. Both compounds demonstrated superior hepatoprotection, normalizing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, attenuating the inflammatory cascade and histopathological damage to an extent comparable to the clinical antioxidant N-acetylcysteine (NAC). Time-resolved analysis reveals a sequential therapeutic mechanism, where early mitogen-activated protein kinases (MAPK) pathway inhibition (within 2 h) precedes downstream ferroptosis and inflammation blockade, demonstrating a temporally orchestrated protective cascade. Mechanistically, KCM and KCF mitigate APAP- and TAA-induced oxidative stress primarily by dampening MAPK signaling, thereby blocking lipid peroxidation, ferroptosis, and pro-inflammatory pathways. This multilayered intervention ultimately halts ALI progression, underscoring their hepatoprotective potential. Collectively, our findings indicate that KCM and KCF exert hepatoprotective effects primarily through inhibition of MAPK, highlighting their potential as therapeutic agents for ALI and warranting further investigation.

Genome sequencing on an intertidal zone-derived Aspergillus flavipes strain revealed its great potential to produce secondary metabolites. To activate the cryptic compounds of A. flavipes, the global regulator flLaeA was knocked out, leading to substantial up-regulation of the expression of two NRPS-like biosynthetic gene clusters in the Delta flLaeA mutant. With a scaled-up fermentation of the Delta flLaeA strain, five compounds, including two previously undescribed piperazine derivatives flavipamides A and B (1 and 2), along with three known compounds (3-5), were obtained by LC-MS guided isolation. The new compounds were elucidated by spectroscopic analysis and electronic circular dichroism (ECD) calculations, and the biosynthetic pathway was proposed on the bias of bioinformatic analysis and 13C isotope labeling evidence. This is the first report to access cryptic fungi secondary metabolites by inactivating global regulator LaeA and may provide a new approach to discovering new secondary metabolites by such genetic manipulation.

A novel and convenient K2S2O8-mediated diiodo cyclization of 1,6-enynes for the facile synthesis of functionalized γ-lactam derivatives has been developed. This reaction features mild and transition-metal-free conditions, which offer a green and efficient entry to synthetically important γ-lactam scaffolds. Mechanistic studies suggest that iodide radicals initiate the cascade cyclic transformation.

A removable acyl group promoted the intramolecular didehydro-Diels-Alder reaction of styrene-ynes under mild reaction conditions is proposed. The reaction is free of metals and catalysts, is easy to perform, and exhibits good functional group tolerance, providing a highly chemoselective approach for obtaining the valuable aryldihydronaphthalene derivatives.

A metal-free, additive-free, and practical method for the synthesis of diiodinated succinimide derivatives has been achieved under mild conditions.

A simple Ag(I)-catalyzed oxidative cyclopropanation of heteroatom-tethered 1,6-enynes for the establishment of valuable functionalized 3-aza-bicyclo[3.1.0]hexane is presented, which allows the formation of multiple chemical bonds in one step under 20 mol % silver(I) catalysts and air conditions. This approach is highly atom economical, easy to perform, and free of external oxidants and features good to excellent yields and gram-scale synthesis. The preliminary study showed that an uncommon silver carbenoid intermediate might be involved in this process.

Excessive stimulation of hepatotoxins and drugs often lead to acute liver injury, while treatment strategies for acute liver injury have been limited. Methyl 6-O-cinnamoyl-α-d-glucopyranoside (MCGP) is a structure modified compound from cinnamic acid, a key chemical found in plants with significant antioxidant, anti-inflammatory, and antidiabetic effects. In this study, we investigated the effects and underlying mechanisms of MCGP on acetaminophen (APAP)- or carbon tetrachloride (CCl4)-induced acute liver injury. As a result, MCGP inhibited cell death and apoptosis induced by APAP or CCl4, and suppressed the reactive oxygen species (ROS) generation stimulated by H2O2 in liver AML12 cells. In vivo, MCGP alleviated APAP/CCl4-induced hepatic necrosis and resumed abnormal aminotransferase activities and liver antioxidase activities. In addition, MCGP depressed APAP- or CCl4-induced oxidative stress through the suppression of CYP2E1 and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. MCGP also enhanced the number of PCNA-positive hepatocytes, increased hepatic PCNA and Bcl-XL, and decreased BAX expression in APAP-/CCl4-intoxicated mice. Furthermore, MCGP activated the GSDMD-N/cleaved caspase 1 pathway. In summary, MCGP might act as a potential therapeutic drug against drug-induced and chemical-induced acute liver injuries, and its underlying mechanisms might engage on the pressing of oxidative stress, refraining of hepatocyte apoptosis, and facilitating of liver regeneration.

The thermal tetradehydro-Diels-Alder (TDDA) reaction for the synthesis of polysubstituted aromatic compounds remains underestimated probably due to the harsh conditions and multiproduct results. Herein, a mild intramolecular TDDA reaction of aryldiyne compounds is presented with linear naphthalenes only, exhibiting good functional group tolerance. The reaction is easy to operate and amenable to multigram-scale synthesis. From the preliminary work, it was found that the mild conditions may be the key to the completely linear product in the reactions.

A novel and convenient method has been developed for the facile synthesis of functionalized succinimide derivatives via intramolecular Alder-ene reaction of 1,6-enynes. This reaction features mild and metal-free reaction conditions, which offers a green and efficient entry to synthetically important succinimide scaffolds. Preliminary mechanistic studies suggest that a diradical intermediate might be involved in this transformation.

Ten PPAPs with unusual skeletons were isolated from H. perforatum. 6 represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights 6 as a promising lead compound in AD drug development.

Nine undescribed shikimate-conjugated meroterpenes, as well as nine known compounds, were isolated from solid cultures of the fungus Guignardia mangiferae, an endophyte obtained from the leaves of Dendrobium nobile. The structures of these undescribed compounds were characterized by analyses of their 1D and 2D NMR and HRESIMS data, and their absolute configurations were assigned by single-crystal X-ray crystallography, electronic circular dichroism (ECD) calculations, modified Mosher's method, and Mo2(OCOCH3)4-induced ECD experiments. Of these compounds, mangnardone A represents the first example of terpene-shikimate-conjugated meroterpenoid with a hydroxy group at C-5. In addition, the X-ray diffraction analysis of mangnardone I is the first example to confirm the structure of bicycloalternarene (BCA) meroterpenoid by single-crystal data. Nine undescribed meroterpenes inhibited nitric oxide (NO) production in LPS-induced RAW 264.7 cells with IC50 values in the range of 4.7-40.0 μM.

A practical and efficient approach for the synthesis of fluorescent 2,3-naphthalimide derivatives has been developed from readily available starting materials via an intramolecular didehydro-Diels-Alder reaction, which proceeded well under room temperature, exhibiting a wide substrate scope and good functional group tolerance. The practicability of this methodology has been verified by one-step synthesis of the environmentally sensitive fluorophore 6-DMN on a gram scale with a shorter time, fewer steps and less waste disposal, and without the utilization of toxic transition metals. The present experimental and computational studies support the crucial role of the propiolimide moiety in the transformation.

An efficient method for N-acylation of amides is described using a pyridine ring as the internal nucleophilic catalyst to give imides in moderate to excellent yields. The methodology provides a facile, air insensitive, and environmentally friendly route to form diversified imide scaffolds, which exist widely in natural products and biologically active materials.

Four undescribed piperazine-2,5-dione derivatives designated janthinolides C-F, and an alpha-pyrone-containing polyketide namely trichopyrone C, were isolated from the extract of the fungus Penicillium griseofulvwn along with four known products. Among them, janthinolide C represents the first naturally occured piperazine-2,5-dione analogue featuring a cleavaged piperazinedione ring with an oxime group, while the structure of janthinolide D possesses a rare N-methoxy group in natural products. Their structures and absolute stereochemistry were elucidated based on spectroscopic data, theoretical NMR and ECD calculations, Snatzke's method, and modified Mosher's method. All compounds were evaluated for in vitro immunosuppression activity in murine splenocytes stimulated by anti-CD3/anti-CD28 mAbs, of which janthinolides B and C showed potential inhibitory activity with IC50 values at 9.3 and 1.3 mu M, respectively.

The study of Aspergillus micronesiensis led to the isolation of three unprecedented cytochalasans (1-3). Dimericchalasine A (1) is the first cytochalasan homodimer fused by a C-20/C-20' single bond. Amichalasines D (2) and E (3) represent a new type of cytochalasan heterotrimer with a decacyclic 5/6/11/5/5/6/5/12/6/5 ring system. Their structures were determined by extensive spectroscopic data and single-crystal X-ray diffraction. The plausible biosynthetic pathways of 1-3 were proposed.