Chemotherapy-induced gastrointestinal toxicity, particularly intestinal barrier disruption and diarrhea, is a major dose-limiting adverse effect with unclear mechanisms. Here, we identify magnesium isoglycyrrhizinate (MIG) as a novel therapeutic agent that ameliorates 5-fluorouracil (5-FU)- and irinotecan-induced intestinal injury by enhancing epithelial barrier integrity. Using MIG as a molecular probe, we revealed a pathogenic mechanism underlying chemotherapy-induced barrier damage. Integrated chemoproteomics (limited proteolysis-mass spectrometry and thermal proteome profiling) analyses revealed direct binding of MIG to the RNA helicase DDX5 (DEAD-box helicase 5), whose expression is markedly increased upon 5-FU-induced injury. Mechanistically, DDX5 destabilizes the G-quadruplex (G4) structure in the CTNNB1 (β-catenin) 5' untranslated region, suppressing β-catenin production and compromising barrier function. Crucially, MIG acts as a novel DDX5 inhibitor that blocks G4 unwinding, thereby restoring β-catenin expression and barrier integrity in a dose-dependent manner. In vivo, MIG outperforms the canonical DDX5 inhibitor supinoxin in mitigating intestinal damage. Taken together, the results of our study not only establish MIG as a promising therapeutic candidate but also delineate the DDX5/CTNNB1 axis as a targetable pathway for treating chemotherapy-induced barrier dysfunction.

BACKGROUND:Hepatocellular carcinoma (HCC) develops in an immunosuppressive tumor microenvironment characterized by NLRP3 overexpression, in which myeloid-derived suppressor cells (MDSCs) are abundantly enriched and play a critical role in compromising T cell-mediated antitumor immunity. Arglabin (Arg), a natural sesquiterpene lactone derived from Artemisia glabella, shows potent anti-HCC potential, yet its direct molecular target responsible for the immunomodulatory effects in HCC remains poorly defined. PURPOSE:To identify its molecular target and delineate the pharmacological mechanisms underlying Arg-mediated anti-HCC immunity. METHODS:NLRP3 and CCR2 expression in myeloid-derived cells was investigated in HCC specimens by western blot, multiplex immunofluorescence and single-cell RNA sequencing data from the GEO database. Molecular interactions between Arg and NLRP3 were assessed through CETSA, SPR, LC-MS/MS, and pull-down assays. In vivo anti-tumor efficacy was evaluated in syngeneic murine models using H22 (BALB/c) and Hepa1-6 (C57BL/6) liver cancer cells. Functional studies included CCK8 and transwell migration assays. Tumor microenvironment composition was analyzed by flow cytometry, and tumor burden was monitored using in vivo bioluminescent imaging. Mechanistically, transcriptional regulation of CCR2 by NLRP3 was investigated through ChIP-qPCR. RESULTS:Here, we demonstrate that Arg suppresses HCC progression in syngeneic murine models by reducing MDSC infiltration and promoting CD8+ T-cell accumulation. MDSC co-implantation and depletion assays confirmed that the therapeutic efficacy of Arg functionally depends on MDSC modulation. Mechanistically, we identified NLRP3 as the direct molecular target of Arg with binding occurring specifically at the Cys280 residue; furthermore, experiments in Nlrp3-/- mice confirmed that NLRP3 is essential for the anti-HCC activity of Arg. Crucially, we reveal that Arg's antitumor effect is independent of the classical NLRP3 inflammasome/IL-1β pathway. Instead, NLRP3 functions through a non-canonical mechanism involving its nuclear translocation and recruitment to the Ccr2 promoter, thereby driving a transcriptional program that orchestrates MDSC trafficking into the tumor microenvironment. Furthermore, NLRP3/CCR2 blockade by Arg potentiates the therapeutic effects of immune checkpoint inhibitors (ICIs) to inhibit tumor growth. CONCLUSION:Our findings establish Arg as an NLRP3-targeting immunomodulator that reshapes the HCC microenvironment. Specifically, Arg binds to the Cys280 residue of NLRP3, thereby inhibiting its nuclear translocation and abrogating the transcriptional regulation of CCR2, which subsequently blocks MDSC trafficking. This effect works together with PD-1 blockade to overcome immune evasion in HCC, providing a strategy for reversing immunosuppression and potentiating immunotherapy.

To evaluate whether first-trimester zinc status is associated with a reduced incidence of preeclampsia (PE) and improved maternal-neonatal outcomes in pregnant women with chronic hypertension. This retrospective observational study included 205 women with chronic hypertension who were stratified into two groups based on their first-trimester supplementation records: a zinc supplementation group (n = 104, receiving 20 mg/day from 12 weeks gestation) and a control group (n = 101, receiving no supplementation). Serum zinc levels, inflammatory markers (TNF-α, hs-CRP), and maternal-neonatal outcomes were assessed and compared between groups. Women in the zinc supplementation group exhibited significantly higher serum zinc levels at 34 weeks (11.64 ± 2.86 vs. 7.85 ± 2.84µmol/L; P < 0.01) and lower levels of TNF-α and hs-CRP (both P < 0.01) compared to the control group. The incidence of PE was significantly lower in the zinc supplementation group (21.15

Inhibiting the contraction of cardiac myosin is an important strategy for treating hypertrophic cardiomyopathy (HCM). However, currently only MYK-461 has been approved for market, and its safety and pharmacokinetic (PK) properties still have deficiencies. Herein, we reported the discovery of a novel and potent cardiac myosin inhibitor Z5-11 through rational structural optimization of MYK-461. Compared with MYK-461, Z5-11 exhibited stronger inhibitory activity against myosin ATPase and could significantly inhibit myocardial cell contraction, as well as alleviate Ang II-induced cardiac hypertrophy. The cytotoxicity assessment on rat myocardial cells showed that Z5-11 exhibited better safety than MYK-461. The PK study revealed that Z5-11 had reasonable half-life time ( t1/2 = 2.74 h), and excellent oral bioavailability ( F = 105.2%). More importantly, Z5-11 can effectively ameliorate transverse aortic constriction (TAC)induced cardiac dysfunction and cardiac hypertrophy and remodeling in mice. These findings suggest that Z5-11 can be developed as a promising drug candidate for treating HCM. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Renal fibrosis, a hallmark of chronic kidney disease (CKD), remains a critical therapeutic challenge with limited effective interventions. Herein, we proposed a multimodal AI-driven Traditional Chinese Medicine (TCM) symptom prediction model (TCM-SPred) and predicted potential herb-symptom associations between herbs and symptoms to obtain agents for treating renal fibrosis. The prediction results of TCM-SPred revealed that a natural guaianolide sesquiterpene lactone derivative dehydrocostus lactone (DCL, a main chemical constituent of Aucklandiae Radix) demonstrated significant anti-fibrotic effects in vivo (unilateral ureteral obstruction) and in vitro (TGF-β1-induced epithelial-mesenchymal transition). DCL directly targeted IQGAP1 to inhibit the Wnt signaling pathway by blocking the interaction between IQGAP1 and CCT3. These findings highlight the potential of DCL as a promising therapeutic candidate for renal fibrosis, providing novel insights into the IQGAP1-CCT3-Wnt signaling axis as a potential target for renal fibrosis intervention.

Lung cancer is the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for 80-85 % of all cases. Thus, while challenging, the exploration of novel therapeutic agents for NSCLC treatment is highly desirable. Pyruvate kinase M2 (PKM2) has been closely associated with disease progression and metastasis in NSCLC, making it a promising therapeutic target. Herein, we report the discovery of a series of N-methylguanidine derivatives that demonstrated potent PKM2 inhibitory activity. In particular, N'-phenanthroline-substituted N-methyl guanidine exhibited notable PKM2 inhibition. Further testing demonstrated that compound 16 exhibited excellent inhibitory effects on A549 and HCC1833 NSCLC cell lines, with IC50 values of 3.36 μM and 9.20 μM, respectively. In vivo antitumor studies further showed that compound 16 significantly inhibited tumor growth in human-derived NSCLC models and mouse lung adenocarcinoma models. Based on these findings, we propose N'-phenanthroline-substituted N-methylguanidine 16 as a promising novel PKM2 inhibitor with potential therapeutic applications for NSCLC.

A cascade colorimetric detection of salivary D-amino acids (DAAs) holds promise for the preliminary screening diagnosis of gastric cancer. Pursuing metal-organic complexes with high peroxidase-mimic (POD-mimic) activity is crucial to enhance diagnosis efficiency. In this work, we developed a straightforward strategy in a "one-pot" process to modulate the POD-mimic activity of CuX-trithiocyanuric acid (CuX-TTCA) complexes. By adjusting the molar ratios of CuX (Cl, Br, and I) and TTCA during synthesis to modify the coordination configuration of Cu(I) in CuX-TTCA, we easily tuned their POD-mimic activities. Among them, CuCl-TTCA-2 with a feeding molar ratio of 2:1 for CuCl:TTCA exhibited remarkable POD-mimic activity attributed to its exposed catalytic active sites and efficient mass transfer ability during catalysis. Long-lived 1O2 was identified as the primary reactive oxygen intermediate. A highly sensitive and selective cascade colorimetric detection platform was developed for two typical DAAs associated with gastric cancer, namely D-proline and D-alanine, achieving limit of detection values of 1.1 and 0.8 mu M, respectively. As a proof-of-concept application, our cascade detection platform demonstrated excellent specificity in distinguishing saliva samples between gastric cancer patients and healthy individuals. The outstanding selectivity and reliable outcomes from DAAs assay make our detection platform highly promising for preliminary screening diagnosis of gastric cancer and patient self-detection applications. Our straightforward strategy for tuning POD-mimic activity provides an in-depth understanding on structure-activity relationship in nanozymes, offering valuable opportunities to advance enzyme-mimic optimization for other potential applications.

Natural products (NPs) are a critical source for drug discovery, and artificial intelligence (AI) is utilized to improve the efficiency of NP-based drug discovery. However, the existing AI-driven models typically generate a library of pseudo-natural products that only covers a small portion of the chemical space and the compounds were also restricted by poor drug-likeness profiles. Herein, the GPT1 is developed to generate diverse pseudo-natural products with excellent validity, uniqueness, and novelty while retaining molecular features similar to the training set. Subsequently, the Augmented Hill-Climb (AHC) strategy is employed to generate synthetically accessible compounds with enhanced drug-likeness. Using the integrated NPDL-GEN model (GPT1 + AHC), compounds G1-G5 were obtained, exhibiting significantly improved drug-likeness profiles. Furthermore, the pseudo-natural products H1-H3 generated via transfer learning also possess potent anti-inflammatory activities. Thus, our developed machine learning models can accelerate NP-based drug discovery.

The activation of nucleotide oligomerization domain-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of various inflammatory diseases. The natural product oridonin possesses a novel mechanism for NLRP3 inhibition and a unique binding mode with NLRP3, but its poor anti-inflammatory activity limits further application. After virtual screening of diverse natural product libraries, dehydrocostus lactone (DCL) was considered as a potential NLRP3 inhibitor. DCL effectively inhibited caspase-1 cleavage and release of IL-1β in mouse and human macrophages at an extremely low concentration of 10 nM, comparable to MCC950. Mechanistically, our study assigned DCL a novel role in disrupting NLRP3 inflammasome assembly and ASC oligomerization. Excluding the influence on potassium/chloride ion efflux, calcium ion influx, and production of mitochondrial ROS, DCL formed a covalent bond with cysteine 280 in NACHT domain of NLRP3, thereby inhibiting the interaction between NLRP3 and NEK7. Furthermore, DCL exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including dextran sulfate sodium-induced colitis, 2,4,6-trinitrobenzenesulfonic acid-induced Crohn's disease, LPS-induced septic shock, and monosodium urate-induced peritonitis. Our findings identify NLRP3 as the direct target of DCL, positioning DCL as a promising lead compound for treatment of NLRP3 inflammasome-related diseases.

Targeting NLRP3 inflammasome has emerged as a promising therapeutic strategy for various inflammatory diseases. In this work, to discover safe and effective novel NLRP3 inhibitors, we designed and synthesized a series of new non-sulfonylurea NLRP3 inflammasome inhibitors. Among them, the representative compound B6 specifically and potently inhibited the activation of NLRP3 inflammasome with an IC50 of 10.69 nM, exhibiting better potency compared to MCC950 (IC50 = 14.08 nM). Furthermore, B6 showed improved tolerability in both human hepatic cell lines and mouse primary hepatocytes (cell viability >95 %) compared to MCC950 (cell viability <82 %) at 500 μM. Mechanistically, B6 did not inhibit LPS-induced priming of the NLRP3 inflammasome, but significantly blocked NLRP3 inflammasome assembly by directly binding to NLRP3 and disrupting the NEK7-NLRP3 interaction. In vivo studies demonstrated that B6 was more effective than MCC950 in multiple NLRP3-driven diseases model, including systemic inflammation, peritonitis, and colitis. These findings suggest that B6 can be developed as a promising drug candidate for treating NLRP3-driven diseases.

BACKGROUND:Pathological cardiac hypertrophy is a characteristic feature of numerous cardiovascular diseases and significantly impacts human health. However, effective treatment options for cardiac hypertrophy are still significantly unmet. Pedunculoside, a pentacyclic triterpenoid saponin from the traditional Chinese herb Ilex rotunda Thunb., exhibits various pharmacological properties such as anti-inflammatory and cardiovascular therapeutic effects, but its anti-hypertrophy efficacy and mechanisms have not yet been reported. PURPOSE:This study aimed to confirm the ameliorating effect of pedunculoside on cardiac hypertrophy and elucidate its underlying mechanism. METHODS:To investigate the effect of pedunculoside on cardiac hypertrophy, we used transverse aortic constriction (TAC) and isoproterenol hydrochloride (ISO) infusion to induce cardiac hypertrophy model in mice. Angiotensin II (Ang II) was used to mimic hypertrophy model in myocardial cells. Then, we utilized a biotin-tagged carabrone chemical probe and validation experiments to pinpoint pedunculoside's key targets. Further, molecular docking study and sites mutation were used to predict and identify the binding modes of pedunculoside to target. Finally, structural optimization was carried out to find new pedunculoside derivatives with stronger anti-hypertrophy activity and binding affinity to the target. RESULTS:Our findings revealed for the first time that pedunculoside treatment significantly attenuated hypertrophic phenotypes in response to TAC and ISO. It also effectively reduced hypertrophy and fibrosis in myocardial cells exposed to Ang II stimulation. Mechanically, we identified transcription factor GATA-6 (GATA6) as a key target of pedunculoside for treating cardiac hypertrophy. Further studies demonstrated that pedunculoside blocks cardiac hypertrophy progression by inhibiting the transcriptional activation of GATA6 on promoting fetal gene expression. More importantly, a new pedunculoside derivative PE-3 with stronger anti-hypertrophy activity and affinity for GATA6 was discovered. CONCLUSION:Our findings suggest that pedunculoside and PE-3 could be developed as promising drug candidates for cardiac hypertrophy treatment.

OBJECTIVE:Formononetin (FM), a flavonoid with potent anti-inflammatory effect, was investigated for its therapeutic potential and underlying mechanisms in allergic asthma (AS). METHODS:An ovalbumin (OVA)-induced murine model of AS was established and treated with FM. Inflammatory responses, mucus secretion, and the activation and migration of type II innate lymphoid cells (ILC2s) were assessed using histological staining, ELISA, flow cytometry, and molecular analysis. The role of the JUN gene was further explored using the JUN agonist 15(S)-HpETE. In vitro assays were conducted to evaluate FM's effects on ILC2 proliferation and cytokine expression. RESULTS:FM significantly alleviated airway inflammation, reduced mucus hypersecretion, and lowered serum IgE levels. It decreased the abundance and activation of ILC2s in lung tissues and suppressed the expression of related cytokines and transcription factors. Notably, FM inhibited the lung-gut axis migration of ILC2s by reducing iILC2 and nILC2 levels in the small intestine and iILC2 levels in the lung. In vitro, FM suppressed ILC2 proliferation and activation. These effects were reversed by 15(S)-HpETE, suggesting a JUN-dependent mechanism. CONCLUSIONS:FM ameliorates AS by inhibiting type II immune responses and ILC2 migration via targeting JUN. These findings suggest FM as a promising candidate for asthma therapy.

The NLRP3 inflammasome is recognized as a critical mediator of innate immunity, which can regulate the maturation of proinflammatory cytokines. Nowadays, several natural products have been confirmed to exhibit potent NLRP3 inhibitory effects and possess novel binding mechanisms with NLRP3. Herein, an AI-driven model (TransGenGRU) is proposed to generate novel natural products with NLRP3 inhibitory activities. Through the modeling of TransGenGRU, two guaianolide sesquiterpenoids (A3 and A8) are identified to possess moderate NLRP3 inhibitory activities. Then, through detailed structure optimization, E1 demonstrates the most potent NLRP3 inhibitory activity (IC50 = 24.42 nM), and the inhibitory effect on the NLRP3 inflammasome is correlated to the assembly of NLRP3/pro-caspase-1/ASC. Notably, E1 is confirmed to covalent-irreversibly interact with Cys280 that is totally different from MCC950. Besides, E1 also demonstrates potent anti-inflammatory activity in vivo, favorable DMPK profiles, and low hERG toxicity. Thus, E1 has been considered a novel and potent NLRP3 inhibitor.

While there have been advancements in the development of innovative PROTACs with sophisticated linkers designed to meet specific requirements, studies on the structure-activity relationships (SAR) of linker length remain a fundamental priority. Although several reliable chemistries for connecting the two ligands-one targeting the protein and the other for E3 ubiquitin ligase-have been established, the potential for utilizing various other methods still needs exploration. In this work, we introduced a concept that employs the SuFEx reaction, a novel family of click chemistry, to quickly construct a small PROTAC library for protein degradation. This was achieved by amidating a sulfonyl fluoride or fluorosulfate precursor (modified with the p300/CBP ligand CPI644) with CRBN ligands that possess amino-carbon chains of varying lengths. The protein degradation effects of the PROTACs created through this strategy were further validated using the p300/CBP overexpressed MDA-MB-468 cell line.

Tau PET tracers are being developed for imaging Alzheimer's disease (AD), primary tauopathies, and potentially screening of cognitively unimpaired elders. A second-generation tau tracer PM-PBB3, currently in Phase 3 clinical trials with FDA Fast Track Designation, shows promise as a broad-spectrum tau imaging agent, but is limited by photoisomerization and binding to amyloid fibrils. Herein, the study reports the development of a better tau probe, BMP-7, created by strategically introducing a methyl group at position 2 of the butadiene scaffold to enhance its chemical and biological properties. BMP-7 exhibits remarkable photostability, showing no significant change in HPLC assays after 6 h of light exposure. Critically, BMP-7 demonstrates increased sensitivity and 4.9-fold greater selectivity than PM-PBB3 for detecting tau pathology in brain sections from transgenic mouse models of AD and 4R tauopathies. Specifically, BMP-7 binds to MC1-reactive pathological tau conformations requiring both C- and N-terminal phosphorylation, which is abolished by in vitro dephosphorylation. Furthermore, BMP-7 readily penetrates the blood-brain barrier and binds to tau pathology in vivo. These studies demonstrate that BMP-7 bearing 2-methyl-butadiene scaffold improves photostability and significantly enhances the sensitivity and selectivity of tau pathology detection, offering substantial advantages for future applications. Therefore, BMP-7 shows potential for further clinical development.

Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast cancer cases; therefore, it is considered a primary therapeutic target for breast cancer. Several therapeutic agents, including selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent ARV-471 has been used to treat locally advanced or metastatic breast cancer in clinical trials. Herein, we designed, synthesized, and evaluated several novel ERα-PROTAC agents. After systematic structural optimization, compound A16 was found to have excellent antiproliferative and ERα-inhibitory activities in the breast cancer cell line MCF-7. A16 selectively degraded ERα (DC50 = 3.78 nM) through the ubiquitin-proteasome pathway in a time- and concentration-dependent manner. It effectively attenuated drug resistance (MCF-7 Y537S cells; IC50 = 1.3 nM), inhibited proliferation, and induced apoptosis in MCF-7 cells. In addition, it exhibited excellent antitumor effects (10 mg/kg/d intraperitoneal injection; total growth inhibition = 80.11 %) and a good safety profile in an MCF-7 xenograft model, highlighting its potential as a novel drug candidate for breast cancer.

Nonalcoholic steatohepatitis (NASH) has become a leading cause of liver fibrosis and hepatocellular carcinoma; however, there are no efficient drugs for NASH therapy. Acetyl-CoA carboxylase (ACC) is a crucial enzyme regulating lipid metabolism that is considered as a potential target for NASH treatment. Allosteric inhibitors target nonfunctional sites, which tend to be highly variable in protein families; thus, allosteric inhibitors are explored as an important source of drug candidates. Herein, several hotspot residues are initially identified by utilizing molecular dynamic simulation, MM-GBSA calculation, and alanine mutation. Then, focusing on the interaction with hotspot residues, several cyclobutane-based ACC allosteric inhibitors are designed, synthesized, and biologically evaluated. Among them, B1 demonstrates potent ACC inhibitory activity in vitro, a higher distribution in liver than in other tissues, and a potent therapeutic effect for NASH in vivo, making it a promising candidate for the treatment of NASH.

Löfgren syndrome (LS) is a unique acute manifestation of sarcoidosis and characterized by erythema nodosum, bilateral hilar lymphadenectasis, and/or bilateral anklearthritis or periarthritis. A 37-year-old female patient with LS presented with fever accompanied by multiple joint swelling and pain, nodular skin erythema, and bilateral hilar lymphadenectasis. The patient had received treatment involving non-steroidal anti-inflammatory drugs and glucocorticoids in other hospitals, but the effects were poor, and the conditions reemerged. The LS duration has lasted for more than 3 months. Following traditional Chinese medicine (TCM) treatment, syndrome differentiation as well as giving patients oral Chinese medicine decoction, the symptoms of the patient were rapidly relieved within one week and did not recur during a six-month follow-up period. This case is the first clinical report of acute sarcoidosis LS treated using TCM and reflects the significant advantages of this form of therapy in emergency treatment

The enormous LysR-type transcriptional regulators (LTTRs), which are diversely distributed amongst prokaryotes, play crucial roles in transcription regulation of genes involved in basic metabolic pathways, virulence and stress resistance. However, the precise transcription activation mechanism of these genes by LTTRs remains to be explored. Here, we determine the cryo-EM structure of a LTTR-dependent transcription activation complex comprising of Escherichia coli RNA polymerase (RNAP), an essential LTTR protein GcvA and its cognate promoter DNA. Structural analysis shows two N-terminal DNA binding domains of GcvA (GcvA_DBD) dimerize and engage the GcvA activation binding sites, presenting the -35 element for specific recognition with the conserved σ70R4. In particular, the versatile C-terminal domain of α subunit of RNAP directly interconnects with GcvA_DBD, σ70R4 and promoter DNA, providing more interfaces for stabilizing the complex. Moreover, molecular docking supports glycine as one potential inducer of GcvA, and single molecule photobleaching experiments kinetically visualize the occurrence of tetrameric GcvA-engaged transcription activation complex as suggested for the other LTTR homologs. Thus, a general model for tetrameric LTTR-dependent transcription activation is proposed. These findings will provide new structural and functional insights into transcription activation of the essential LTTRs.

Euryales Semen (ES) is a highly nutritious food with low digestibility, which is closely associated with its endogenous phenolic compounds. In this study, five phenolic compounds (naringenin, isoquercitrin, gallic acid, epicatechin and quercetin) with high concentrations in ES were selected to prepare starch-polyphenol complexes. Subsequently, the effects of endogenous polyphenols on the structure, physicochemical properties and digestion characteristics of ES starch were studied using multiple techniques. The addition of phenolic compounds markedly reduced the in vitro digestibility, swelling power, gelatinization enthalpy, while increased the solubility of ES starch. Fourier-transform infrared spectroscopy and X-ray diffraction analysis showed that phenolic compounds interacted with the starch through non-covalent bonds. Five phenolic compounds inhibited α-amylase activity through a mixed competitive inhibition mechanism, with the inhibition potency ranked as follows: quercetin > epicatechin > gallic acid > isoquercitrin > naringenin. The spectroscopic analysis and molecular dynamics simulations confirmed that five phenolic compounds interacted with the amino acid residues of α-amylase through hydrogen bonding and hydrophobic interactions, caused α-amylase static fluorescence quenching, and altered its conformation and microenvironment. This study provides a better understanding of the interaction mechanisms between ES starch and polyphenols, and supports the development of ES as a food that lowers sugar levels.