Atherosclerosis (AS) is a chronic vascular disease with complex pathological mechanisms, characterized primarily by the formation of aortic plaques. Calenduloside E (CE), a compound isolated from Aralia elata, exhibits beneficial cardiovascular activities. Our previous studies have shown that CE can protect human umbilical vein endothelial cells (HUVECs) from damage induced by oxidized low-density lipoprotein (ox-LDL) through binding to the target protein HSP90AB1 in cell lysate. However, there is currently no direct research demonstrating the anti-atherosclerotic effect of CE in vivo, and its mechanism of action and direct targets in cell remain unclear. This study demonstrates that CE exhibits potent anti-atherosclerotic activity. In vivo, CE shows significant anti-atherosclerotic activity by inhibiting plaque formation in ApoE-/- mice. Using the CC-ABPP strategy, we employed the activity-based probe CE-P to pull down the targets of CE in live HUVECs, and proteomic analysis identified phosphoglycerate kinase 1 (PGK1) as a potential direct target of CE. The interaction between the two was verified by Surface Plasmon Resonance (SPR), Cellular Thermal Shift Assay (CETSA), and molecular dynamics simulation studies. Additionally, we designed and synthesized 18 CE derivatives for PGK1 activity assays and found that CE and its derivatives can significantly inhibit PGK1 enzymatic activity. Notably, K1 exhibited the best activity in protecting HUVECs against ox-LDL-induced damage at 0.78 μM. In summary, these results indicate that CE is a promising anti-atherosclerotic agent, and PGK1 is a potential direct target of CE. PGK1 may serve as a highly promising therapeutic target for anti-atherosclerosis in the future.

Background and ObjectiveHigh-altitude polycythemia (HAPC) and its associated cardiac complications, induced by hypobaric hypoxia (HH), pose significant clinical challenges. Xinnaoxin (XNX) tablets are clinically utilized for these conditions; however, their integrated multi-target mechanisms remain poorly understood. This study aims to elucidate the novel mechanisms and therapeutic potential of XNX against HAPC and HH-induced cardiac injury. For the first time, we employed a combined strategy of systems pharmacology and multi-level analysis to comprehensively investigate how XNX confers synergistic protection by modulating both the hematopoietic microenvironment and myocardial signaling networks.MethodsThe metabolites of XNX were systematically identified, and its chemical profile was established using UPLC-Q-TOF-MS. An HH mouse model was generated by simulating a high-altitude hypoxic environment. Comprehensive assessments included complete blood parameters, hemorheology, the proportion and apoptosis of CD71+ bone marrow cells, and serum levels of erythropoietin (EPO) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Cardiac injury was evaluated through histopathology, echocardiography, oxidative stress indicators (MDA, T-AOC, CAT, SOD), and Western blot analyses of key signaling pathways, including phosphorylation status of MAPK, JNK, ERK, IκBα, NF-κB, and Akt, as well as the expression of apoptosis-related proteins Bax and Bcl-2.ResultsXNX significantly reversed HH-induced elevations in red blood cell count, hemoglobin, hematocrit, white blood cell count, and plasma viscosity, while reducing serum EPO levels. Notably, XNX decreased the bone marrow population of CD71+ cells, indicating inhibition of “ineffective erythropoiesis.” Regarding cardioprotection, XNX markedly alleviated myocardial injury, reduced oxidative stress (MDA), enhanced antioxidant enzyme activities, and suppressed pro-inflammatory cytokine release. Mechanistically, XNX coordinately modulated the phosphorylation levels of multiple signaling pathways (MAPK, JNK, IκBα, NF-κB, Akt) and regulated the Bax/Bcl-2 balance, thereby creating a signaling environment favorable for cardiomyocyte survival and repair.ConclusionXNX exerts its therapeutic effects through a dual mechanism: (1) ameliorating HAPC at its source by regulating EPO expression and enhancing bone marrow erythropoietic efficiency, and (2) counteracting HH-induced cardiac injury via multi-target modulation of the MAPK-related signaling network. These findings clarify the pharmacological basis of XNX and provide a theoretical foundation for developing multi-pathway synergistic therapies for high-altitude hypoxia-related cardiovascular diseases.

Background: Atherosclerosis (AS) serves as the primary pathological basis for cardiovascular disease-related deaths worldwide, posing a severe threat to public health security. Heat shock protein 90 (HSP90) plays a crucial regulatory role in the pathological progression of AS, emerging as a potential target for anti-atherosclerosis drug development in recent years. Calenduloside E (CE) is a pentacyclic triterpenoid saponin isolated from Aralia elata (Miq.) Seem. Previous studies have confirmed its anti-atherosclerotic activity, but its weak efficacy and narrow therapeutic index limit its clinical application. In this study, the CE scaffold was hybridized with a ticagrelor-derived fragment to enhance anti-atherosclerotic activity. In this study, the CE scaffold was hybridized with a ticagrelor fragment to achieve improved activity. Methods: Based on the principle of molecular hybridization, CE was linked to the active fragment of ticagrelor via a PEG chain. Ten CE derivatives were synthesized by modifying the sugar substituents. In vitro experiments were conducted to detect cytotoxicity and protective activity against ox-LDL-induced HUVECs injury. Molecular docking and Surface Plasmon Resonance (SPR) assays were used to evaluate the interaction between CE derivatives and the known target HSP90β. Combined with Microscale Thermophoresis (MST), SwissTargetPrediction, and molecular docking, other potential targets of CE derivatives were identified. Results: In the ox-LDL-induced HUVECs injury model, all compounds except C2 and C9 exhibited protective activity. Among these compounds, compound C5 exhibited the optimal protective effect, with an EC50 value of 1.44 μM. Molecular docking results revealed that both C5 and CE could bind to HSP90β by forming hydrogen bonds with the key amino acid Asp93. Additionally, SPR results indicated that C5 and CE had similar binding affinities to HSP90β, with dissociation constants (KD) of 1.73 μM and 1.72 μM, respectively. MST demonstrated that C5 binds to HSP90β with an affinity 111 times higher than that of ticagrelor. SwissTargetPrediction and molecular docking identified P2Y12 as another potential target of derivative C5. Conclusions: Compound C5 exerts protective effect against ox-LDL-induced HUVECs injury by targeting HSP90β. Its effective concentration is significantly improved compared with that of the parent CE, which provides a possibility for reducing clinical dosage and toxic side effects in subsequent studies. Furthermore, C5 may exert its effects by targeting another potential target, P2Y12, offering references for the rational design of novel anti-atherosclerotic drugs.

Inducing adult cardiomyocyte proliferation to repair the infarcted heart remains a major therapeutic challenge. While metabolic reprogramming is known to drive regeneration, the specific organelle-level mechanisms governing this process, particularly the crosstalk between mitochondria and lipid droplets (LDs), remain elusive. Here, we identify Heat Shock Cognate 71 kDa Protein (Hsc70) as a critical physiological "metabolic brake" that maintains adult cardiomyocytes in a terminally differentiated state and suppresses cell cycle re-entry by tethering mitochondria to LDs via Mitofusin 2 (Mfn2). Using Ginsenoside Rb2, a bioactive small molecule identified from a clinically effective formula (Shuangshen Ningxin), we demonstrate that Rb2 directly binds to Hsc70 (KD ≈ 32 µM) and disrupts the Hsc70-Mfn2 interaction. This disruption pharmacologically uncouples the remaining mitochondria-LD contacts to f release this physiological barrier, restores metabolic homeostasis, and reactivates cardiomyocyte proliferation in myocardial infarction (MI) rats. Crucially, these regenerative effects were abrogated by AAV9-mediated Hsc70 overexpression, confirming Hsc70 as the non-redundant therapeutic target. Furthermore, a retrospective analysis of 60 patients treated with the Rb2-containing intervention showed significantly improved cardiac outcomes, highlighting the broad cardioprotective and clinical utility of this therapeutic strategy. Our findings reveal a fundamental mechanism linking organelle dynamics to tissue regeneration and highlight Hsc70 as a druggable target for heart failure treatment.

INTRODUCTION:Platelet activation is a key contributor to myocardial ischemia/ reperfusion (MI/R) injury. Although hydroxysafflor yellow A (HSYA) possesses cardioprotective and antiplatelet properties, its specific mechanisms in modulating platelet activation during MI/R remain unclear. OBJECTIVES:This study investigated how HSYA attenuates MI/R injury by regulating platelet activation. METHODS:An MI/R model was established in mice via ligation of the left anterior descending coronary artery. The regulatory effects of HSYA on platelet activation and mitochondrial function were evaluated via flow cytometry. The mechanisms were analyzed via platelet proteomics. Platelet autophagy was characterized via transmission electron microscopy and western blotting. RESULTS:HSYA significantly attenuated MI/R injury by reducing the myocardial infarct size, improving cardiac function, and decreasing platelet accumulation in the myocardium. HSYA also suppressed platelet activation and enhanced platelet mitochondrial function. Platelet proteomic analysis indicated that the beneficial effects of HSYA were associated primarily with the modulation of proteins involved in energy metabolism and autophagy pathways. Furthermore, HSYA was found to regulate platelet autophagy, as evidenced by both a change in the number of autophagosomes and altered expression of key autophagy-related proteins, including ATG4A, GLIPR2, P62, and LC3. DISCUSSION:Our study provides novel mechanistic insights into how HSYA confers cardioprotection against MI/R injury, highlighting its clinical potential by demonstrating that its effects are mediated at least in part through the modulation of platelet energy metabolism and autophagy. CONCLUSION:HSYA alleviates MI/R injury by inhibiting platelet activation, which is associated with the restoration of mitochondrial function and the modulation of autophagy in platelets.

Myocardial infarction (MI) induces a strong injury response, resulting in a collagen-dominated scarring. A persistent myocardial fibrotic response induces heart failure. Myocardial fibroblasts are responsible for the deposition and remodeling of collagen and are important targets for limiting the fibrotic process after myocardial infarction. Iminostilbene (ISB), a small molecule and synthetic intermediate of carbamazepine, exhibits potent antiapoptotic, anti-inflammatory, and antioxidative effects. However, its role in cardiac fibrosis, target binding, and underlying mechanisms remains unclear. Objective: To evaluate the effect of iminostilbene on myocardial fibrosis after myocardial infarction (MI), we explored its target mechanism. Methods: The rat model of myocardial infarction was established by permanent ligation of the left anterior descending branch of coronary artery in vivo, and then iminostilbene or captopril was given for 2 weeks. Primary myocardial fibroblasts (CFs) were stimulated with 10 nM TGF-β1 in vitro to establish a myocardial fibrosis model. The PAL-CC-ABPP technique was used to fish for iminostilbene binding targets to further clarify its antifibrosis effect and mechanism. Results: Iminostilbene significantly improved cardiac function and inhibited pathological myocardial fibrosis in rats after myocardial infarction. Histological analysis, immunofluorescence, and Western blot results showed that iminostilbene treatment significantly decreased the expression of extracellular matrix (ECM)-associated proteins α-SMA and Collagen I in myocardial tissue. Further in vitro results confirmed that iminostilbene inhibited fibroblast activation. According to proteomic analysis, galectin-3 is a potential target of iminostilbene, and the specific binding was verified by competitive experiments and DARTS. In addition, in terms of the biological function of iminostilbene to galectin-3, iminostilbene decreased the expression of galectin-3 after myocardial infarction. Iminostilbene has an inhibitory effect on TGF-β1/smad3 downstream pathway of galectin-3, which can reduce the expression of TGF-β1 and inhibit the phosphorylation of Smad3 to alleviate myocardial fibrosis. Conclusion: Iminostilbene can be used to inhibit CFs activation through the Gal3/TGF-β1/Smad3 pathway, improve cardiac function, and alleviate cardiac fibrosis.

Carthamus tinctorius L. is widely used for cardiovascular and cerebrovascular diseases. Hydroxysafflor yellow A (HSYA), its major quinochalcone glycoside, is effective against myocardial ischaemia/reperfusion injury (MI/RI), while other compounds' roles remain unclear. This study established chemical fingerprints of 9 C. tinctorius populations via ultra-performance liquid chromatography, evaluated cardiomyocyte protective effects using Cell Counting Kit-8 assays and performed spectrum-effect analysis integrating grey correlation analysis and partial least-square (PLSR), combined with compound identification via ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Seven potential active components were screened: HSYA, kaempferol-3-O-β-sophorose, saffloquinoside A, roseoside, quercetin-3,7-di-O-β-D-glucoside, 6-hydroxykaempferol-3,6-di-O-β-D-glucoside, saffloquinoside C. These may be key anti-MI/RI substances in C. tinctorius, with specific pharmacological mechanisms to be further verified, providing a reference for exploring its representative active components.

BACKGROUND:Aspirin is frequently employed for the prevention of cardiovascular events, but its clinical utility is hindered by the risk of severe gastrointestinal injury when taken orally. Fufanglongxuejie capsules (FFLXJ), a Chinese patent medicine known for promoting wound healing and alleviating congestion and pain, may offer a promising solution to this clinical challenge. METHODS:Using network pharmacology, candidate targets of FFLXJ, gastrointestinal disorders, intersection targets, and associated signaling pathways were examined. Prior to the creation of myocardial ischemia-reperfusion (MI/R) models, male Sprague-Dawley (SD) rats were orally administered FFLXJ and/or aspirin for a consecutive month. Subsequently, serum motilin (MTL), gastrin (GAS), HE staining, transmission electron microscopy analysis, and western blot analysis were performed on the blood samples or gastric tissues. Molecular docking analysis on core targets and relative compounds was conducted using Discovery Studio software. The expressions of core targets were verified by Western blot. RESULTS:Compared with aspirin-treated MI/R rats, FFLXJ restored downregulated serum MTL and GAS levels and lessened aspirin-induced gastrointestinal lesions. Network pharmacology research revealed that the top 4 core targets were TNF, IL-10, PTGS2, and VEGFA. In MI/R rats, aspirin treatment markedly increased the level of stomach IL-10, while FFLXJ administration decreased the expression of PTGS2 and IL-10 compared with aspirin-treated group. CONCLUSION:Oral aspirin harmed the gastrointestinal mucosa in MI/R rats; however, FFLXJ was able to mitigate the damage. The protective property of FFLXJ was related to the regulation of inflammation.

Endoplasmic reticulum stress (ERS) and apoptosis are hallmark pathological features of myocardial ischemia-reperfusion injury (MIRI). Lamin A/C, a nuclear lamina protein associated with cardiac disorders, has been implicated in ERS and apoptosis regulation, yet its role in MIRI remains elusive. Meanwhile, P4HB, an ERS-associated chaperone, may interact with lamin A/C to modulate MIRI progression. We hypothesized that lamin A/C interacts with P4HB to modulate MIRI progression. We assessed the distribution of P4HB and lamin A/C in MIRI SD rat hearts and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated primary neonatal rat cardiomyocytes (PNRCMs). By knocking down lamin A/C expression, we examined the impact of lamin A/C on P4HB distribution, ERS and apoptosis induced by OGD/R modeling. STRING network analysis and protein-protein docking were employed to predict the structural basis of lamin A/C/P4HB interaction. Our results demonstrated OGD/R treatment triggered P4HB nuclear envelope translocation, ERS activation, and apoptosis in PNRCMs, while those effects were attenuated by lamin A/C knockdown. The physical interaction between lamin A/C and P4HB in cardiac tissue was observed under both normal and MIRI conditions. The P4HB-lamin A/C interaction may be dynamically modulated by calreticulin. Collectively, our findings propose that lamin A/C regulates P4HB to mitigate OGD/R-induced ERS and apoptosis, potentially through a calreticulin-mediated dynamic mechanism.

This study aims to elucidate the chemical composition of the dichloromethane extract from the aerial parts of Ferula ferulaeoides (DEAFF) and to explore its biological activities. The composition of DEAFF was analyzed by UHPLC-Q-Orbitrap-MS/MS. Then, the carrageenan-induced tail thrombosis model, xylene-induced ear swelling model, and acetic acid-induced writhing model were established to evaluate the relevant activities of DEAFF. Network pharmacology research and molecular docking were conducted to elucidate the pathways and key targets underlying the multiple activities of DEAFF. A total of 30 chemical constituents were tentatively identified in DEAFF based on UHPLC-Q-Orbitrap-MS/MS analysis. Pharmacodynamic results showed that DEAFF significantly reduced the proportion of thrombus in the tail of mice, effectively alleviated ear swelling, improved the degree of ear tissue lesions, and significantly reduced the number of writhing movements in mice, indicating that it has multiple pharmacological effects such as antithrombosis, anti-inflammation, and analgesia. Network pharmacology studies have shown that multiple pathways such as the PI3K-Akt signaling pathway and the MAPK signaling pathway play a crucial role in the pharmacological effects of DEAFF. In this study, the chemical components of DEAFF were preliminarily identified, and its effects on thrombosis prevention, anti-inflammation, and analgesia were systematically investigated.

Since the proposal of the"central dogma,"various types of RNA have been discovered,including messenger RNA(mRNA),ribosomal RNA(rRNA),and transfer RNA(tRNA).These RNAs are further classified into coding and non-coding RNAs(ncRNAs).The modernization of research on traditional Chinese medicines(TCMs)has led to the increasing availability of whole-genome sequences for medicinal plants and the initiation of RNome(ie,the complete set of all RNA species)projects for TCMs.In this article,from the perspective of mRNAs involved in the transmission and expression of genetic information and ncRNAs involved in the regulation of gene function in herbal taxa,we emphasize the impor-tance of the discovery of novel functional ncRNA com-ponents in TCMs through the construction of systematic herbal mRNA libraries and an herbal ncRNA functional database for TCMs.This research area could revolution-ize research and development focused on nucleic acid drugs and pesticides,opening up a new dimension for the modernization of TCMs.

Background Diabetic cardiomyopathy (DCM), a consequential cardiovascular complication of diabetes mellitus, drives progressive myocardial fibrosis and cardiac dysfunction, culminating in heart failure (HF). Ginsenoside Rc (Rc) has significant antidiabetic and cardiovascular protective properties, but its potential to improve DCM is unclear. Purpose The aim of this study was to explore the mechanism of Rc against DCM. Methods The DCM model was established in db/db mice to evaluate the effects of Rc on metabolic and adipokine indicators in serum, and echocardiography and histological examinations were used to detect cardiac function in the mice. A lipotoxicity model of H9c2 cells was established using PA to verify the protective effect of Rc on cardiomyocytes, reduce lipotoxicity and improve mitochondrial function. The effect of Rc on adiponectin (APN) was demonstrated in 3T3 - L1 cells. Lipid metabolomics was used to explore the possible pathways by which Rc improves DCM. Quantitative reverse transcription polymerase chain reaction (qRT‒PCR) and western blot (WB) were used to detect gene and protein expression in mouse hearts and H9c2 cells. Results Rc reduced body weight, glycemia, dyslipidemia, and inflammatory mediator levels in db/db mice. It alleviated myocardial fibrosis and lipid accumulation and protected against lipotoxicity-induced damage in H9c2 cells. Furthermore, Rc enhanced mitochondrial function in lipotoxic H9c2 cells while suppressing reactive oxygen species (ROS) generation. Rc also reduced hepatic lipid accumulation in db/db mice while decreasing lipid droplet accumulation in 3T3-L1 cells. Critically, Rc elevated circulating APN levels in both db/db mice and 3T3-L1 cells, which increased the expression of APPL1, LKB1 and AdipoR1 in both the hearts of db/db mice and lipotoxicity-induced H9c2 cells. Lipid metabolomics analysis of db/db mouse serum and urine revealed that Rc primarily regulated autophagy-related pathways. Rc significantly increased the number of autophagic vesicles in H9c2 cells with lipotoxicity and promoted autophagy pathways in both the hearts of db/db mice and lipotoxic H9c2 cells. This increased AMPKα2 phosphorylation, Beclin1 expression and the LC3II/LC3I ratio while reducing p62 expression. Conclusion Collectively, these data indicated that Rc could rectify glucose/lipid metabolic perturbations, attenuate oxidative stress and inflammation, and restore mitochondrial functionality. Rc promoted APN secretion and activated the AdipoR1/APPL1/LKB1/AMPKα2 signaling pathway, further enhancing autophagy, increasing the ratio of LC3II/LC3Ⅰ and the expression of Beclin1, and decreasing the expression of p62, which reduced lipotoxicity and demonstrated potential for preventing and treating DCM.

As a racemate, 3-n-butylphthalide (NBP) can be separated into its S- and R-enantiomers, with S-NBP reported to exhibit superior bioactivity. To develop more potent anti-stroke agents with enhanced bioavailability, we therefore employed S-NBP as the lead compound. Through structural modification and hybridization with ligustrazine (TMP), 20 novel S-NBP-TMP hybrids were designed and synthesized. In vitro screening for neuroprotection using OGD/R-injured HT22 cells and primary hippocampal neurons identified compounds S8g, S8h, and S8i. At 12.5 μM, these compounds significantly enhanced cell viability recovery compared to both their racemates and NBP. Among them, S8i exhibited the most potent neuroprotective activity, outperforming even S-NBP. Subsequent mechanistic studies demonstrated that S8i effectively attenuated OGD/R-induced mitochondrial damage and oxidative stress, while also reducing both neuronal apoptosis and necrosis. Molecular docking revealed that S8i effectively occupies the Keap1 binding pocket for Nrf2 and forms four hydrogen bonds with Arg380, Arg415, and Ser555. Moreover, S8i exhibits favorable BBB permeability, as its Pe value (21.95 × 10-6 cm/s) significantly exceeds the penetration threshold. In vivo studies demonstrated that S8i ameliorated cerebral ischemia-reperfusion injury, restored cerebral blood flow, and protected cerebral vasculature in MCAO/R model mice. Furthermore, at doses of 30 and 60 mg/kg, S8i exhibited significantly superior efficacy to NBP (90 mg/kg). Additionally, S8i downregulated Keap1 expression and upregulated the expression of Nrf2 and its downstream factors, HO-1 and NQO-1 in vivo. In summary, S8i demonstrates significantly enhanced neuroprotection versus its racemate, NBP, and S-NBP, positioning it as a highly promising lead compound for ischemic stroke therapy.

AIMS:To investigate the effect of Notoginseng leaf triterpenes (PNGL) on diabetic cardiomyopathy by suppressing lipotoxicity, and to explore the possible underlying mechanisms. To study the potential mechanism by which PNGL decrease lipotoxicity and hence affect diabetic cardiomyopathy. METHODS:For 8 weeks, diabetic db/db mice were given either a high-dose (100 mg/kg daily) or low-dose (50 mg/kg daily) of PNGL intragastrially. Body weight, blood glucose, body fat, iWAT weight, BAT weight level, serum lipids, hormones involved in the metabolism of glucose and lipids, inflammatory variables, and antioxidant factors were among the many parameters that were assessed. In addition, cardiac function and myocardial enzyme levels were examined. Cardiac pathological structure, cardiomyocyte apoptosis levels and lipid accumulation were detected. To look into the potential mechanism and function of PNGL in diabetic cardiomyopathy (DCM). RESULTS:PNGL treatment improved obesity, serum lipids, glucose and lipid metabolism, antioxidant function, and reduced inflammation and cardiomyocyte apoptosis in db/db mice. Cardiac function and myocardial enzyme levels were also improved by PNGL. In addition, PNGL alleviated cardiac histopathology, myocardial fibrosis and lipid accumulation in cardiomyocytes. Further research demonstrated that PNGL may play a protective role in diabetic cardiomyopathy by alleviating lipid metabolism. CONCLUSIONS:PNGL protects cardiac structure and function in diabetic cardiomyopathy by inhibiting lipotoxicity, and the mechanism is partially related to the adiponectin pathway activation.

[This corrects the article DOI: 10.3389/fphar.2020.567238.].

Ischemic stroke is a life-threatening disease, its pathological progression involves multiple factors, including oxidative stress, apoptosis, and ferroptosis. Our previous study demonstrated that hybridizing N-butylphthalide (NBP) with ligustrazine (TMP) yielded promising anti-ischemic compounds. In this study, we further introduced a triazole structure into NBP-TMP hybrids and synthesized 20 novel compounds. Their neuroprotective activities were evaluated on OGD/R induced SH-SY5Y cells and primary hippocampal neurons, leading to the identification of preferred compounds 8a, 8b and 8d at the concentration of 6.25 μM, which surpassed the neuroprotective activity of the positive control NBP. Among them, 8a exhibited the highest protective activity, with a protection percentage of 75.6 %. Further mechanistic studies revealed that compounds 8a, 8b and 8d maintained intracellular redox homeostasis to resist oxidative stress and inhibit apoptosis in vitro. Specifically, compound 8a exerted neuroprotective effects by modulating the KEAP1-NRF2 pathway: it bound to KEAP1, enhanced NRF2 dissociation and nuclear translocation, facilitated the generation of downstream antioxidant factors, thereby reducing intracellular ‌reactive oxygen species (ROS) levels and effectively protecting neuronal mitochondria. Finally, in vivo experiments demonstrated that compound 8a (20 mg/kg) significantly ameliorated cerebral injury in rats with ischemia-reperfusion injury. Furthermore, it reduced cerebral oxidative stress by modulating the KEAP1-NRF2 pathway and inhibited neuronal apoptosis and ferroptosis in the brain, which is consistent with the results in vitro. In conclusion, our results indicated that 8a serves as a promising candidate for stroke treatment and may facilitate the development of future anti-ischemic drugs.