Phytomedicine [JOURNAL]
Sun
200 papers
Ginsenoside Rd attenuates renal aging and fibrosis through inhibition of angiotensin II type 1 receptor signaling.
Setiawan T, Julianto NM, Wijaya YT … +12 more , Fadjaray TF, Wirawan LM, Muhammad JA, Muvva C, Park K, Kim SW, Lee EY, Lee J, Lee MR, Ou Y, Zhao X, Kwon HY
Phytomedicine · 2026 Jun · PMID 42314349 · Publisher ↗
BACKGROUND: Renal cellular senescence-characterized by the accumulation of extracellular matrix and the consequent development of fibrosis-is a major contributor to accelerated renal aging. Despite its clinical significa...
BACKGROUND: Renal cellular senescence-characterized by the accumulation of extracellular matrix and the consequent development of fibrosis-is a major contributor to accelerated renal aging. Despite its clinical significance, effective antifibrotic therapies remain limited due to the complex pathophysiology of kidney fibrosis. PURPOSE: This study aimed to identify a novel pharmacological agent that counteracts renal fibrosis and cellular senescence associated with aging and injury. METHODS: We evaluated the effects of ginsenoside Rd (GRd) in aged mice and multiple kidney injury models, including cisplatin-induced acute kidney injury and adenine-induced chronic kidney disease. Renal function, fibrosis, and senescence markers were assessed following GRd administration. RESULTS: GRd administration attenuated renal damage, reduced senescent cell burden, and suppressed fibrotic remodeling in aged mice and in multiple kidney injury models. Mechanistically, GRd disrupted angiotensin II (Ang II)-mediated signaling by acting as a competitive antagonist at the Ang II type 1 receptor (AT1R), thereby blocking downstream oxidative stress and DNA damage response pathways involving p16, p21, and p53. Consequently, GRd treatment resulted in a reduced accumulation of senescent cells and a decrease in the expression of senescence-associated secretory phenotype (SASP) factors in vivo. GRd-treated kidneys ultimately exhibited significantly reduced fibrosis and improved functional outcomes. CONCLUSION: These findings highlight GRd as a promising therapeutic candidate for preventing or ameliorating renal aging and fibrosis in both acute and chronic kidney injury contexts.
Cucurbitacin B induces immunogenic cell death and activates adaptive immunity in cutaneous melanoma via the ROS-STAT3-eIF2α/IRE1 pathway.
Xu M, Dai X, Li R … +8 more , Zhang D, Li Z, Zhang J, Luo X, Liu X, He J, Ma J, Yang Z
Phytomedicine · 2026 Aug · PMID 42314266 · Publisher ↗
BACKGROUND: Immunotherapy is the first-line treatment for advanced cases in cutaneous melanoma (CM). However, nearly half of patients develop resistance or recurrence, mainly attributed to an immunosuppressive tumor immu...
BACKGROUND: Immunotherapy is the first-line treatment for advanced cases in cutaneous melanoma (CM). However, nearly half of patients develop resistance or recurrence, mainly attributed to an immunosuppressive tumor immune microenvironment (TIME). Cucurbitacin B (CuB), a tetracyclic triterpenoid from Cucurbitaceae plants, has broad-spectrum anticancer activity, yet its role and mechanism in regulating CM-associated immunogenic cell death (ICD) and TIME remain unclear. PURPOSE: To investigate the antitumor effects of CuB on CM, and explore its mechanisms in inducing ICD. STUDY DESIGN AND METHODS: The anti-tumor activity and safety of CuB were evaluated using in vitro and in vivo experiments. Molecular biological assays were performed to detect ICD markers, TIME remodeling, and changes in immune cell subsets. The core mechanism was validated by integrating bioinformatics, molecular techniques, and targeted inhibitors. RESULTS: 1. CuB induces ICD in CM cells with markedly elevated release of damage-associated molecular patterns (DAMPs) both in vitro and in vivo. 2. CuB reprograms the TIME, promotes dendritic cell (DC) maturation, induces macrophage polarization toward the M1 phenotype, enhances effector T cell infiltration, reduces the proportions of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and downregulates PD-L1 expression in tumor tissues and PD-1 expression in splenocytes. 3. Mechanistically, CuB induces ICD via the Reactive oxygen species (ROS)-STAT3-eIF2α/IRE1-mediated endoplasmic reticulum stress (ERS) axis. CONCLUSION: CuB is a potential candidate for combination with chemotherapeutics or immune checkpoint inhibitors, offering a novel melanoma treatment strategy.
Jiawei Shoutai Pill promotes embryo implantation via PPAR signaling and endometrial microbiota remodeling: An integrative multi-omics study.
Zhang Y, Cao X, Ma Y … +4 more , Guo Z, Lian F, Song J, Sun Z
Phytomedicine · 2026 Aug · PMID 42314265 · Publisher ↗
BACKGROUND: Recurrent implantation failure (RIF) remains a major barrier to successful assisted reproductive technology, given the lack of effective, mechanism-informed interventions to enhance endometrial receptivity. J...
BACKGROUND: Recurrent implantation failure (RIF) remains a major barrier to successful assisted reproductive technology, given the lack of effective, mechanism-informed interventions to enhance endometrial receptivity. Jiawei Shoutai Wan (pills) (JWSTW), a modified formulation of the classic Shoutai Pill (STP) used in reproductive medicine, has not been systematically evaluated in the treatment of RIF, and its bioactive components and molecular targets remain largely unclear. PURPOSE: To determine whether JWSTW improves implantation competence and to identify the pathways associated with its effects. MATERIALS AND METHODS: A mifepristone-induced embryo implantation dysfunction (EID) rat model was established to evaluate implantation outcomes, uterine histology, and markers of endometrial receptivity and vascular perfusion. Bulk uterine transcriptomics and peripheral blood serum untargeted metabolomics were integrated with liquid chromatography-tandem mass spectrometry (LC-MS) based component profiling, network pharmacology, multi-omics correlation analysis, uterine cavity microbiota profiling and structure-based computational analyses. Key pathway molecules were further assessed using targeted molecular experiments. A retrospective cohort of RIF patients undergoing assisted reproduction was analyzed for ultrasound-derived endometrial receptivity parameters before and after treatment. RESULTS: JWSTW administration improved implantation outcomes in EID rats, characterized by the upregulation of multiple receptivity- and perfusion-associated tissue markers. Integrated multi-omics analyses identified peroxisome proliferator-activated receptor (PPAR) signaling and lipid metabolism as significantly enriched pathways, supported by corresponding gene-metabolite correlations. Animal experiments using PPAR agonists (rosigitazone) and antagonists (T0070907) further confirmed that the PPAR pathway is a primary target of JWSTW. JWSTW was also associated with structured changes in the uterine cavity microbiota, with enriched taxa and predicted functions aligned with lipid metabolism related pathways. LC-MS/MS characterization identified sweroside and loganic acid as major circulating constituents, while computational analyses prioritized a PPAR-centered target network with favorable binding affinity and structural stability. In the retrospective RIF cohort (n = 100), JWSTW was associated with increased endometrial thickness and improved Doppler-derived perfusion indices. CONCLUSION: These results demonstrated that JWSTW enhances endometrial receptivity and promotes embryo implantation in RIF by modulating the PPAR-lipid metabolism axis and remodeling the uterine microbiota. Consequently, our study advances the pharmacodynamic understanding of JWSTW and deepens the comprehension of its underlying mechanistic basis in RIF. Furthermore, these findings provide an innovative Traditional Chinese Medicine-based treatment strategy, offering a promising therapeutic avenue for patients with RIF.
Deciphering the complex mechanisms of action of lead detoxification by the green microalga Chlorella vulgaris.
Jin C, Gündoğdu S, Hegazi NM … +8 more , Lu X, Elbadawi M, Kampf C, Klauck SM, Rahali S, Achenbach N, Hegazy MF, Efferth T
Phytomedicine · 2026 Aug · PMID 42314264 · Publisher ↗
BACKGROUND: Lead (Pb) intoxication necessitates detoxification strategies that are efficacious and devoid of the adverse effects characteristic of synthetic chelators. The green microalga Chlorella is of particular inter...
BACKGROUND: Lead (Pb) intoxication necessitates detoxification strategies that are efficacious and devoid of the adverse effects characteristic of synthetic chelators. The green microalga Chlorella is of particular interest because it exerts diverse metal-binding properties and is rich in micronutrients that collectively support detoxification with a potentially more favorable safety profile. HYPOTHESIS: We hypothesized that employing an experimental model with enhanced Pbtransport capacity by cells transfected with a cDNA encoding the divalent metal transporter 1 (DMT1) and a Chlorella dietary supplement could help elucidate the specific mechanisms underlying its detoxification action. METHODS: To identify the optimal species, the extracts from Chlorella vulgaris (C. vulgaris) and Chlorella pyrenoidosa (C. pyrenoidosa) supplements were compared in metabolomic profiling by HPLC-HRMS/MS. The DMT1-overexpressing cell model was constructed by assessing the detoxification efficacy of C. vulgaris extract using cell viability and the Trolox equivalent antioxidant capacity assays. Pb concentration was measured by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). To map the complex mechanisms of action, transcriptomic analyses were performed and analyzed using Ingenuity Pathway Analysis (IPA) and validated by western blotting and fluorescence microscopy. RESULTS: Metabolite profiling and antioxidant capacity assay identified the C. vulgaris aqueous extract as superior. It attenuated Pb-induced cytotoxicity and was prone to promote cellular Pbexport in DMT1-transfected cells. Transcriptomics revealed that Pbexhibited a signature of hepatorenal toxicity, and the aqueous extract rescued the zinc finger protein's function. Western blot and fluorescence microscopy validated that C. vulgaris water extract may orchestrate a multifaceted defense: rectifying Pb-induced autophagic flux blockage, alleviating ferroptotic stress, triggering an adaptive metabolic shift via protein lipoylation and a p-STAT3-mediated survival pathway, jointly preserving microtubule integrity. CONCLUSION: These findings advance prior research by first providing a comprehensive detoxification mechanism framework of C. vulgaris, positioning C. vulgaris as a promising, multi-mechanism supplement for mitigating Pbpoisoning.
Dihydrotanshinone I suppresses glycolysis and gastric cancer growth by targeting the nuclear FBXW11/LTN1/PKM2 axis.
Nie Y, Bai X, Zhang M … +3 more , Liu X, Jiang T, Zhang G
Phytomedicine · 2026 Aug · PMID 42314263 · Publisher ↗
BACKGROUND: Gastric cancer (GC) is a major global health problem, particularly in Asia. Dihydrotanshinone I (DHT), a naturally derived and commercially available compound isolated from Salvia miltiorrhiza, exhibits poten...
BACKGROUND: Gastric cancer (GC) is a major global health problem, particularly in Asia. Dihydrotanshinone I (DHT), a naturally derived and commercially available compound isolated from Salvia miltiorrhiza, exhibits potential anti-GC activity through the modulation of cancer metabolism. PURPOSE: This study aimed to investigate the anti-GC effects of DHT and elucidate the molecular mechanisms through which DHT regulates glycolysis. STUDY DESIGN: Integrated molecular profiling, functional experiments, and clinical sample analyses were employed to evaluate the pharmacological effects and mechanism of DHT in gastric cancer. METHODS: The pharmacological targets and signaling pathways regulated by DHT were identified using RNA sequencing, chromatin immunoprecipitation sequencing, and immunoprecipitation-mass spectrometry. Functional validation was performed using in vitro assays and in vivo models. Clinical GC specimens were analyzed for associations between target gene expression, clinicopathological features, and patient prognosis. RESULTS: DHT selectively inhibited GC cell proliferation at low concentrations while sparing normal gastric epithelial cells. Nuclear FBXW11 was identified as a direct target and was upregulated in GC tissues. This upregulation was correlated with advanced TNM stage and poor prognosis. The suppression of nuclear FBXW11 expression reduced glycolysis, invasion, and proliferation. Mechanistically, DHT promoted the LTN1-mediated ubiquitin-proteasome degradation of PKM2, thus suppressing glycolysis. CONCLUSION: Dihydrotanshinone I suppresses GC progression via the FBXW11/LTN1/PKM2 axis, highlighting its potential as a metabolism-targeting phytochemical with low toxicity and translational relevance. Unlike previously reported DHT mechanisms involving oxidative stress, DNA damage, or immune modulation, our findings reveal a previously unrecognized nuclear ubiquitination-mediated metabolic regulatory axis in gastric cancer.
Pterostilbene ameliorates benzo[b]fluoranthene-induced lung injury by suppressing Toll-like receptor 4/nuclear factor kappa-B pathway and mitochondria-mediated apoptosis.
Bao Q, Sun Y, Wei M … +5 more , Zhou S, Yao Y, You J, Zhang L, Xiong J
Phytomedicine · 2026 Jun · PMID 42308992 · Publisher ↗
BACKGROUND: Benzo[b]fluoranthene is a polycyclic aromatic hydrocarbon widely present in grilled, smoked, fried foods and incomplete tobacco combustions, and was reported to impact the cardiovascular and pulmonary health,...
BACKGROUND: Benzo[b]fluoranthene is a polycyclic aromatic hydrocarbon widely present in grilled, smoked, fried foods and incomplete tobacco combustions, and was reported to impact the cardiovascular and pulmonary health, while pterostilbene, a phytochemical commonly found in grapes, blue berries and Pterocarpus santalinus, is capable of modulating inflammatory responses, oxidative stress, and apoptosis. PURPOSE: This study evaluated if pterostilbene mitigates benzo[b]fluoranthene-induced lung injury through anti-inflammatory, antioxidant, and anti-apoptotic activities. METHODS: In vivo studies utilized C57BL/6J Nifdc mice (n=8 per group). The six experimental groups included: a sham control (corn oil), a benzo[b]fluoranthene group (100 mg/kg), a pterostilbene group (50 mg/kg), and three co-treatment groups receiving both BbF (100 mg/kg) and PT at 12.5, 25, or 50 mg/kg. Concurrent in vitro analyses in BEAS-2B and 16HBE bronchial epithelial cells comprised immunological evaluations, oxidative stress measurements, and mechanistic studies targeting mRNAs and proteins associated with inflammation, antioxidant response, and apoptosis. RESULTS: In mice, oral administration of pterostilbene reduced benzo[b]fluoranthene-induced inflammatory cell infiltration in the lung, elevated the expressions of anti-inflammatory and antioxidant factors in both the lung tissues and the serum, and regulated key oxidative stress and inflammatory proteins NF-κB and HO-1. In the BEAS-2B and 16HBE cells, pterostilbene treatment decreased the proportions of sub-G1 phase cells and apoptotic cells, restored mitochondrial membrane potential suppressed by benzo[b]fluoranthene exposure, increased the levels of antioxidant enzymes (CAT, GSH, GPx), and upregulated the expressions of anti-apoptotic protein Bcl-2 and antioxidant proteins Nrf2 and HO-1. CONCLUSION: Pterostilbene can protects the respiratory tract against injury through a multi-mechanism mode of action. Its synergistic anti-inflammatory, antioxidant, and anti-apoptotic activities collectively alleviate oxidative stress, suppress inflammatory responses, and inhibit programmed cell death, thereby preserving respiratory epithelial integrity and function.
AI-driven discovery of synergistic combinations from Psoralea corylifolia fruit for treating osteoporosis.
Liu CL, Li MR, Long J … +5 more , Qian ST, Zhang C, Li P, Jiang Y, Li HJ
Phytomedicine · 2026 Jun · PMID 42308991 · Publisher ↗
BACKGROUND: Estrogen-deficient osteoporosis demands safe and effective therapies. Psoralea corylifolia fruit (PCF), a phytoestrogenic herbal medicine for osteoporosis, lacks clarified key active components and synergisti...
BACKGROUND: Estrogen-deficient osteoporosis demands safe and effective therapies. Psoralea corylifolia fruit (PCF), a phytoestrogenic herbal medicine for osteoporosis, lacks clarified key active components and synergistic combinations, which limits its application. PURPOSE: This study established an AI-driven stepwise strategy to identify anti-osteoporotic synergistic combination from PCF, quantify their synergism, and validate pharmacodynamics, thus providing a reference for complex disease treatment. METHODS: An AI-driven stepwise integrated strategy was proposed: Ⅰ) Artificial intelligence-assisted preliminary screening of PCF active components via dual estrogenic/anti-osteoporotic models; Ⅱ) molecular simulation (docking/dynamics) for secondary screening of candidate components; Ⅲ) multi-dimensional evaluation for precision targeting of lead components; Ⅳ) Chou-Talalay method used to determine synergism (combination index, CI<0.9), additivity (0.9≤CI≤1.1), or antagonism (CI>1.1). Ultimately, the pharmacodynamic activity of the screened synergistic combination was validated through systematic in vitro and in vivo pharmacodynamic evaluations, combined bioequivalence analysis based on 90% confidence interval. RESULTS: Machine learning (ML) screening identified 20 active components, narrowed to 6 via molecular simulations. Three leads viz neobavaisoflavone (NBIF), bavachin (BA) and isobavachalcone (IB) were finalized. The NBIF+BA synergistic combination with significant synergism (CI<0.9) showed superior efficacy to individual components, and equivalence to PCF extract (90% confidence interval: 78.12%-132.15%). CONCLUSION: This AI-driven strategy successfully identified a synergistic combination of NBIF+BA with potent anti-osteoporotic effects from PCF, presenting a promising approach for the treatment of complex diseases.
3,3'-Diindolylmethane ameliorates muscle atrophy by modulating mitochondrial function and calcium homeostasis.
Gao X, Feng X, Feng G … +8 more , Zhong J, Liu Y, Pan S, Wang Z, Miao S, Lu R, Sun K, Ye Y
Phytomedicine · 2026 Jun · PMID 42308990 · Publisher ↗
BACKGROUND: Sarcopenia is a chronic degenerative condition characterized by the progressive loss of muscle mass and function. Current therapeutic strategies exhibit limited therapeutic efficacy and present substantial ch...
BACKGROUND: Sarcopenia is a chronic degenerative condition characterized by the progressive loss of muscle mass and function. Current therapeutic strategies exhibit limited therapeutic efficacy and present substantial challenges in ensuring sustained patient compliance. Although mitochondrial dysfunction is a confirmed biomarker of skeletal muscle atrophy, the exact molecular mechanisms governing this process have yet to be fully elucidated. Notably, store-operated calcium entry (SOCE) not only serves as a pivotal mechanism in mitochondrial calcium signaling but has also been recently identified as a key contributor to sarcopenia. Novel formulations of 3,3'-Diindolylmethane (DIM) shows improved pharmacokinetics with minimal side effects and high bioavailability, thereby enhancing therapeutic adherence. However, previous studies have not fully unraveled the therapeutic potential of DIM for managing sarcopenia or its precise molecular mechanisms. PURPOSE: This research was conducted to systematically explore the therapeutic efficacy of DIM in sarcopenia through three research models and hierarchically clarify the underlying molecular mechanisms. METHODS: We used three distinct models: a murine model of muscle atrophy induced by long-term injection of dexamethasone (DEX), a worm model of natural aging in Caenorhabditis elegans (C. elegans), and a cell model of C2C12 myotube atrophy intervened by dexamethasone. The primary evaluation measures encompassed histopathological examination, immunofluorescence, fluorescent probes, western blot and flow cytometry. RESULTS: DIM demonstrated therapeutic promise by enhancing grip strength and myofiber quality in mice, extending lifespan of C. elegans. DIM attenuated DEX-induced myotube atrophy while promoting myotube differentiation. Mechanistically, DIM mitigated mitochondrial dysfunction by inhibiting excessive reactive oxygen species generation and decline of mitochondrial membrane potential caused by muscle atrophy. Concurrently, DIM enhanced the expression of stromal interaction molecule 1 to activate SOCE, thereby modulating calcium homeostasis and promoting muscle cell differentiation, effectively preventing further muscle atrophy. CONCLUSIONS: Importantly, this study constitutes the inaugural demonstration across three distinct experimental models (murine muscle atrophy, Caenorhabditis elegans and cellular systems) that DIM activates and enhances the SOCE mechanism by improving mitochondrial function, thereby restoring disrupted calcium homeostasis and alleviating muscle atrophy. These findings offer novel mechanistic insights and promising intervention targets regarding how natural phytochemicals counteract sarcopenia, while concurrently underscoring the therapeutic potential of DIM in alleviating muscle atrophy.
Wuzi Yanzong Pill improves Parkinson's disease via miR-146a-5p/USP3/NF-κB axis.
Xu L, Feng Z, Li Z … +6 more , Qin S, Yang L, Xiao B, Ma C, Fan H, Chai Z
Phytomedicine · 2026 Jun · PMID 42308989 · Publisher ↗
BACKGROUND AND PURPOSE: Neuroinflammation, characterized by dysregulated activation of microglia, is a hallmark of Parkinson's disease (PD). Nevertheless, therapeutic strategies aimed at the mechanism of inflammation res...
BACKGROUND AND PURPOSE: Neuroinflammation, characterized by dysregulated activation of microglia, is a hallmark of Parkinson's disease (PD). Nevertheless, therapeutic strategies aimed at the mechanism of inflammation resolution remain limited. STUDY DESIGN AND METHODS: This study integrated PD clinical cohorts, MPTP-induced and miR-146a-induced mouse models, as well as LPS-stimulated and miR-146a-activated cell models. Combined with omics analysis, behavioral detection and molecular biology experiments, we systematically evaluated the anti-inflammatory protective effects of Wuzi Yanzong Pills (WYP). The active plant metabolites of WYP were identified using a combination of UHPLC-Q-Exactive-MS/MS, AP-SMALDI Orbitrap MSI, and pharmacokinetic analysis. RESULTS: In PD patients, WYP significantly improved motor dysfunction, inhibited pro-inflammatory cytokines, and elevated neurotransmitter levels. Exosomal miRNA sequencing analysis indicated that miR-146a-5p may serve as a biomarker for PD and is positively correlated with disease severity. Animal experiments further showed that WYP improved motor symptoms and neuroinflammation in MPTP- and miR-146a-induced PD mice models. A dual-luciferase reporter assay confirmed ubiquitin specific peptidase 3 (USP3) as a direct target gene of miR-146a-5p. In an LPS-activated BV2 microglial cell model, WYP intervention reduced the content of miR-146a-5p in cell-derived exosomes and mitigated their pro-inflammatory damaging effects on neuronal cells. Component analysis revealed that 16 plant metabolites in WYP can enter the bloodstream, among which 11 can cross into the brain. Notably, geniposidic acid, hyperoside, kaempferol, protocatechuic acid, and schisandrol A significantly suppressed the expression of pro-inflammatory factors in BV2 cells, suggesting that they may be the main active components underlying the anti-inflammatory effects of WYP. CONCLUSION: WYP improves PD by regulating the miR-146a-5p/USP3/NF-κB pathway. Meanwhile, the active plant metabolites of WYP have been identified. These findings provide experimental evidence for WYP as a potential therapeutic agent for PD.
Treatment of sleep disorders with traditional Chinese medicine: Pharmacological activities and mechanisms.
He Z, Wang R, Dai X … +5 more , Li J, Geng J, Zhou J, Du R, Pei H
Phytomedicine · 2026 Jun · PMID 42308988 · Publisher ↗
BACKGROUND: All living organisms require sleep for maintaining and restoring essential bodily functions. However, rising life pressures have led to an increasing incidence of sleep disorders (SD), primarily insomnia, eve...
BACKGROUND: All living organisms require sleep for maintaining and restoring essential bodily functions. However, rising life pressures have led to an increasing incidence of sleep disorders (SD), primarily insomnia, even accompanied by depression and anxiety. Compared with conventional therapies that often pose side effects, Traditional Chinese Medicine (TCM) offers multi-target, low-cost alternatives with proven clinical safety and efficacy. PURPOSE: To systematically review the active components, mechanisms, and clinical evidence of TCM for SD, guiding future drug development. STUDY DESIGN AND METHODS: A comprehensive literature search was conducted from 2015 to 2025 in PubMed, ScienceDirect, Web of Science, and CNKI databases using keywords "SD", "insomnia", "Traditional Chinese medicine", herbal medicine", "Chinese patent medicine", "Traditional Chinese medicine prescriptions", and specific Chinese medicine names (like ginseng, Ziziphi Spinosae Semen and Wolfiporia cocos), and the acquired literature was comprehensively organized. RESULTS: Owing to its natural origins and clinical effectiveness, TCM possesses unique advantages in treating SD and its associated emotional problems by regulating central nervous system (CNS) neurotransmitters, sleep related cytokines, hypothalamic-pituitary-adrenal (HPA) axis secreted hormones, and the abundance of gut microbiota. CONCLUSION: TCM demonstrates significant potential in the treatment of SD. Future research should focus on elucidating specific mechanisms of action and enhancing clinical evidence, thereby facilitating the integration of TCM into clinical practice for improved SD management.
Arisaematis Rhizoma protects against refractory status epilepticus via inhibiting caspase-1-mediated neuroinflammation.
Zhang S, Guo X, Wang R … +15 more , Ye J, Ye H, Yan M, Shan Q, Sun M, Gong Y, Wu Z, Han F, Du Y, Liang J, Jin Q, Xie S, Tang Y, Chen Z, Xu C
Phytomedicine · 2026 Jun · PMID 42308987 · Publisher ↗
BACKGROUND: Status epilepticus (SE), the most severe form of epilepsy, is frequently refractory to first-line diazepam (DZP) therapy. Activation of neuroinflammation is closely associated with the development of refracto...
BACKGROUND: Status epilepticus (SE), the most severe form of epilepsy, is frequently refractory to first-line diazepam (DZP) therapy. Activation of neuroinflammation is closely associated with the development of refractory SE. AR, a traditional Chinese medicine, reportedly possesses anti-neuroinflammatory properties. PURPOSE: This study aimed to investigate the effects of AR extract in two animal models of refractory SE and explore its underlying mechanisms. METHODS: The main components of AR were identified by LC-MS. Pilocarpine- and kainic acid (KA)-induced refractory SE models were established to evaluate AR efficacy. Neuronal protection was assessed via NeuN staining. Network pharmacology and molecular docking were applied to predict therapeutic targets and active components. Potential mechanisms were verified by WB, immunohistochemistry, in vitro electrophysiology, and caspase-1 mice. RESULTS: AR extract attenuated acute seizures in pentylenetetrazol and KA models. Co-administration of AR with DZP effectively terminated refractory SE induced by pilocarpine or KA. AR also conferred neuroprotection against SE-induced hippocampal neuronal loss. Network analysis indicated involvement of inflammatory pathways, particularly caspase-1/IL-1β signaling. Immunohistochemistry confirmed that AR suppressed caspase-1 upregulation in refractory SE mice. It also directly inhibited caspase-1-mediated increases in neuronal excitability and excitatory synaptic transmission; these effects were absent in caspase-1 mice, where AR lost its efficacy. Finally, schaftoside, a key active component of AR, replicated AR's therapeutic effects and exhibited strong binding affinity to caspase-1. CONCLUSION: Our findings reveal that AR terminates refractory SE by inhibiting caspase-1, suggesting its potential as a therapeutic strategy for this neurological emergency.
Clinopodium chinense extract alleviates ferroptosis of endometrial epithelial cells via regulating TLR4/SLC7A11 signaling pathway in lipopolysaccharide-induced endometritis.
Tao H, Liu Y, Su Q … +4 more , Tang R, Wang J, Li L, Huang Q
Phytomedicine · 2026 Aug · PMID 42308762 · Publisher ↗
BACKGROUND: Clinopodium chinense (Benth.) O. Kuntze (C. chinense) is one of the traditional Chinese medicine that has been used in treating gynecological bleeding. Recent research showed that total extract of C. chinense...
BACKGROUND: Clinopodium chinense (Benth.) O. Kuntze (C. chinense) is one of the traditional Chinese medicine that has been used in treating gynecological bleeding. Recent research showed that total extract of C. chinense (TEC) played an important role in the treatment of endometritis, but the mechanism of which need to be further revealed. Ferroptosis has served as a pathogenic mechanism in endometritis. The aim of this experiment was to clarify whether TEC ameliorates endometritis by attenuating ferroptosis and to elucidate its underlying mechanism. PURPOSE: The purpose of this research is to investigate the therapeutic effect and underlying mechanism of TEC suppressing ferroptosis of endometrial epithelial cells in endometritis. METHODS: The mouse model of endometritis was established via intrauterine injection of lipopolysaccharide (LPS, 5 mg/ml) into female mice. Primary mouse endometrial epithelial cells (MEECs) were isolated from pregnant female mice and subjected to in vitro experiments. High-resolution mass spectrometry (HRMS) identified the bioactive ingredients in TEC. Transcriptomic and proteomic analyses revealed the potential targets of TEC against endometritis. Specifically, HE staining evaluated the pathological changes in the uterus. Immunohistochemistry staining assayed the expression of CD138, SLC7A11 and GPX4. The mitochondrial morphology was observed by transmission electron microscope (TEM). Prussian blue staining and Ferro orange staining evaluated the content of Fe. The contents of ROS, Fe, LDH, GSH, MPO and pro-inflammatory cytokine levels including IL-1β, IL-6, TNF-α were detected using kits. Molecular docking evaluated the binding activities between active compounds of TEC and potential targets. Mechanistically, the expression of TLR4, p-p53, SLC7A11, ACSL4 and GPX4 were evaluated using western blotting or immunofluorescence staining. RESULTS: The nine active compounds in TEC were detected. Transcriptomic and proteomic analyses showed that TEC may alleviate endometritis by attenuating ferroptosis. The pharmacological results demonstrated that TEC alleviated endometrial pathological damage, decreased CD138 expression, reduced MPO activity and pro-inflammatory cytokine levels. TEC also diminished mitochondrial shrinkage and increased membrane integrity in uterine tissue. And, TEC decreased ROS, Fe, GSH contents, and suppressed ferroptosis of endometrial epithelial cells. Furthermore, the molecular docking technique revealed that hesperidin, didymin and quercetin, which were the major active components of TEC could bind to TLR4 and SLC7A11. Western blotting analysis further verified that TEC down-regulated TLR4, p-p53 and ACSL4 expression, up-regulated SLC7A11 and GPX4 expression. CONCLUSIONS: TEC alleviates LPS-induced inflammatory damage in both mouse uterine tissues and MEECs by suppressing ferroptosis, the underlying mechanisms of which were related to inhibiting TLR4/SLC7A11 signaling pathway.
Catalpol reverses doxorubicin-induced cognitive decline, neuroinflammation, and restores synaptic integrity.
Le ACD, El-Khatib SM, Tran BM … +3 more , Chan FY, Chan A, Acharya MM
Phytomedicine · 2026 Aug · PMID 42308761 · Publisher ↗
BACKGROUND: Cancer therapy-related cognitive impairments (CRCI) are detrimental for millions of cancer survivors. Chemotherapy induces neuroinflammation and reduces synaptic integrity, contributing to CRCI. Our past pre-...
BACKGROUND: Cancer therapy-related cognitive impairments (CRCI) are detrimental for millions of cancer survivors. Chemotherapy induces neuroinflammation and reduces synaptic integrity, contributing to CRCI. Our past pre-clinical animal studies showed synaptic loss, including postsynaptic density protein 95 (PSD-95) and dynamin-1, that were associated with CRCI. Our human observational data showed reduced plasma dynamin-1 in breast cancer patients receiving chemotherapy. Since these proteins promote synaptic trafficking and plasticity that contribute to cognitive function, augmenting and protecting synaptic integrity represents a viable solution to reverse CRCI. Catalpol, a phytochemical, isolated from Rehmannia glutinosa (Gaertn.) Libosch. ex DC. plant root, has been shown to increase PSD-95 and dynamin-1, and reduce microglial activation in the injured brains. PURPOSE: This study tested the neuroprotective impact of oral catalpol treatment in the mouse model of CRCI. METHODS: Adult wild-type mice received either vehicle or chronic chemotherapy, doxorubicin (Adriamycin®, 3 mg/kg, intraperitoneal) once weekly for four weeks. 72 h after the last Adriamycin injection, mice were treated with catalpol (0.5 mg/ml corresponding to 50 mg/kg) for one month in drinking water (in addition to 50 mg/kg daily injections for the first 6 days), followed by cognitive function testing. RESULTS: Administration of catalpol to Adriamycin-exposed mice significantly improved cognitive performance in the spatial recognition memory task. Hippocampal tissue analysis revealed that catalpol significantly reduced microglial activation and prevented loss of synaptic machinery proteins, including dynamin-1 and PSD-95, in the Adriamycin-exposed brains. Catalpol also restored hippocampal neurogenesis and neuronal plasticity-related cFos. CONCLUSION: This data provides pre-clinical evidence of the feasibility of oral administration of catalpol as a phytopharmaceutical candidate for CRCI.
Activation of PPARγ/FGF21 signaling axis with Puerarin reprograms tumor lipid metabolism, attenuating malignancy in colon cancer.
Tang Y, Zhou P, Ding Y … +5 more , Wei Y, Li Y, Qu H, Yang Y, Xia J
Phytomedicine · 2026 Aug · PMID 42302645 · Publisher ↗
BACKGROUND AND PURPOSE: Colorectal cancer (CRC) stands as the third most prevalent malignancy and represents the second primary cause of cancer-associated deaths. Lipid metabolic reprogramming constitutes a cancer hallma...
BACKGROUND AND PURPOSE: Colorectal cancer (CRC) stands as the third most prevalent malignancy and represents the second primary cause of cancer-associated deaths. Lipid metabolic reprogramming constitutes a cancer hallmark, distinguished by markedly elevated lipid synthesis and extensive lipid-droplet accumulation. Puerarin, an isoflavone from pueraria lobata, shows lipid metabolism regulation and anticancer activity. In this investigation, we examined whether puerarin could modulate lipid metabolism for the treatment of CRC and delved into the underlying mechanisms. EXPERIMENTAL APPROACH: A network pharmacology-bioinformatics framework was developed to determine the potential targets of puerarin in CRC. For in vitro experiments, HCT-116, HCT-116/Oxa, SW480 and SW620 CRC cell models were chosen. We utilized western blotting (WB), quantitative real-time PCR (qRT-PCR), cell counting kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay, Transwell, lipid-droplet immunofluorescence (IF) assay, RNA-sequencing analysis and flow cytometry analysis to examine the molecular mechanisms by which puerarin modulates lipid metabolism in CRC treatment. For in vivo experiments, we established two murine paradigms-a dextran sulfate sodium (DSS)-driven orthotopic CRC model and a subcutaneous xenograft model-and comprehensively evaluated the in vivo efficacy of puerarin against murine CRC, together with its underlying mechanisms, by colonoscopy, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (H&E), immunohistochemical (IHC), IF and WB analyses. KEY RESULTS: Our findings established that peroxisome proliferator-activated receptor gamma (PPARγ) as a bona fide target through which puerarin rewireed lipid metabolism in CRC. Loss of PPARγ was tightly linked to aggressive disease progression, whereas puerarin-by activating PPARγ-boosted downstream fibroblast growth factor 21 (FGF21) expression, suppressed the phosphoinositide 3-Kinase (PI3K)/ protein kinase B (AKT)/ mechanistic target of rapamycin (mTOR) axis, and thereby disrupted tumor lipogenesis. This signaling rewiring attenuated malignant growth and chemoresistance both in vitro and in vivo. CONCLUSION AND IMPLICATIONS: Puerarin halted the malignant progression of CRC by reprogramming tumor lipid metabolism. Puerarin thus hold promise as a clinically deployable lipid-centric agent that could synergistically potentiate conventional anticancer drugs.
Hydroxygenkwanin exerts osteoprotective effects by regulating LRG1-PJA1-PML axis.
Wu X, Liu L, Fan S … +5 more , Sun Y, Wang C, Lu K, Sun H, Liu M
Phytomedicine · 2026 Aug · PMID 42302644 · Publisher ↗
Osteoporosis, especially postmenopausal osteoporosis driven by estrogen deficiency, remains a major public health burden due to elevated fracture risk. Current treatments are often limited by adverse effects and cost, pr...
Osteoporosis, especially postmenopausal osteoporosis driven by estrogen deficiency, remains a major public health burden due to elevated fracture risk. Current treatments are often limited by adverse effects and cost, prompting interest in safer natural compounds. Here, we identify hydroxygenkwanin (HGK), a Daphne genkwa-derived flavonoid, as a potent osteoprotective compound with an unprecedented mechanism of action. Femoral RNA sequencing from ovariectomized (OVX) mice revealed leucine-rich alpha-2-glycoprotein 1 (LRG1) as the most differentially expressed gene following HGK treatment, suggesting a core mechanism. Bioinformatics analysis and co-immunoprecipitation assays identified PRAJA ring finger ubiquitin ligase 1 (PJA1) as the E3 ubiquitin ligase that mediates the degradation of promyelocytic leukemia protein (PML), a key osteogenic regulator. In vivo, HGK effectively attenuated OVX-induced bone loss and improved bone microarchitecture through the LRG1-PJA1-PML axis. Mechanistically, we demonstrate that HGK directly binds to LRG1 (as validated by CETSA, pull-down assays, and molecular dynamics simulations), an interaction that potentiates the association of LRG1 with the E3 ubiquitin ligase PJA1. This sequestration of PJA1 prevents its interaction with, and subsequent ubiquitination of, PML. The resulting stabilization of PML promotes osteoblast differentiation in an oxidative stress milieu. Collectively, these results reveal a critical LRG1-PJA1-PML axis in OP and establish HGK as a first-in-class candidate that leverages this pathway for therapeutic intervention.
Eucalyptus globulus fruit extract alleviates MASLD via modulation of the IRE1α/XBP1s pathway.
Liu Y, Lou M, Wei Y … +4 more , Zhang K, Li W, Kong L, Yang M
Phytomedicine · 2026 Aug · PMID 42302643 · Publisher ↗
BACKGROUND: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is on the rise, while pharmacotherapeutic options remain limited. Eucalyptus globulus fruit is an herbal medicine with empiric...
BACKGROUND: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is on the rise, while pharmacotherapeutic options remain limited. Eucalyptus globulus fruit is an herbal medicine with empirical lipid-modulating properties. However, its therapeutic potential against MASLD remains uninvestigated. PURPOSE: Assess the anti-MASLD efficacy of E. globulus fruit extract (EgE), identify its major active constituent, and uncover underlying mechanisms. METHODS: EgE was evaluated for lipid-lowering activity in free fatty acid (FFA)-stimulated hepatocytes, and assessed for therapeutic effects in two mouse models of MASLD. Phytochemical investigation was conducted to characterize its major constituents. The underlying mechanism was investigated using transcriptomics, drug affinity responsive target stability (DARTS), pathway inhibition/knockdown assays, molecular docking, etc. RESULTS: EgE markedly decreased FFA-elevated lipid content in vitro. Consistently, it substantially ameliorated glucose and lipid metabolic disorders, attenuated hepatic steatosis, and mitigated associated pathological liver injury in vivo. Hepatic transcriptomic profiling revealed marked enrichment of lipid metabolism and endoplasmic reticulum stress (ERS) pathways, and subsequent mechanistic studies further identified EgE as an IRE1α regulator that activates the adaptive IRE1α/XBP1s signaling, thereby restraining pathological ERS. Macrocarpal A (MA) was identified as the primary bioactive component. It binds the h1 pocket of IRE1α to increase its dimeric form, elevate XBP1s levels, and thereby exert lipid-lowering efficacy. CONCLUSION: EgE exhibits potent anti-MASLD effects by activating the adaptive IRE1α/XBP1s axis, representing a promising novel therapeutic candidate for MASLD management. Its major constituent MA directly engages the h1 pocket of IRE1α to increase dimeric IRE1α - a previously unrecognized binding mode.
FBXO11 enhances colorectal cancer progression through TMBIM6 stabilization: Echinacoside as a natural inhibitor.
He C, Xu J, Bai Y … +8 more , Yu M, Chen K, Zhao Y, Gao X, Luo H, Li T, Weng C, Li G
Phytomedicine · 2026 Aug · PMID 42302642 · Publisher ↗
BACKGROUND: FBXO11, an E3 ubiquitin ligase, has been implicated as a potential oncogenic driver in multiple cancer types; however, its biological function and therapeutic significance in colorectal cancer (CRC) remain po...
BACKGROUND: FBXO11, an E3 ubiquitin ligase, has been implicated as a potential oncogenic driver in multiple cancer types; however, its biological function and therapeutic significance in colorectal cancer (CRC) remain poorly defined. METHODS: TCGA and TNMplot databases were analyzed to assess FBXO11 expression and prognostic significance in CRC. Immunohistochemistry validated findings in 100 clinical CRC specimens. Functional impacts of FBXO11 knockdown were tested in vitro (proliferation, colony formation, migration, invasion) and in vivo. Structure-based virtual screening identified Echinacoside (ECH) as an FBXO11 inhibitor, with binding confirmed by CETSA and DARTS assays. Mechanistic studies, including in vitro pull-down and site-directed mutagenesis, interrogated FBXO11-TMBIM6 interactions and ubiquitination cascades. RESULTS: FBXO11 was significantly upregulated in CRC tissues and correlated with poor prognosis. Its suppression inhibited CRC malignant behaviors in vitro and in vivo. ECH bound FBXO11 and triggered its ubiquitin-proteasomal degradation, suppressing CRC progression dependent on FBXO11 inhibition, reducing tumor burden in xenografts without systemic toxicity. Mechanistically, in vitro assays confirmed a direct FBXO11-TMBIM6 interaction. ECH or FBXO11 knockdown disrupted this axis, impairing K63-linked ubiquitination specifically at the K15 residue of TMBIM6, which subsequently unshielded it for K48-linked ubiquitination and proteasomal degradation of TMBIM6. CONCLUSION: FBXO11 is a critical regulator of CRC progression via stabilization of TMBIM6 and highlights ECH as a promising therapeutic degrader targeting the FBXO11-TMBIM6 axis.
Liquiritigenin ameliorates circadian rhythm-mediated osteoblast differentiation through Rorα and Nr1d1 signaling pathways.
Chu H, Li Y, Liang Z … +6 more , Wang Y, Luo Y, Gan J, Li G, Wang Z, Xu B
Phytomedicine · 2026 Jun · PMID 42302427 · Publisher ↗
Circadian rhythm disorders can destroy the balance of bone metabolism and hence closely related to bone metabolic diseases. To further explore the relationship between circadian rhythm and bone metabolism, the sleep depr...
Circadian rhythm disorders can destroy the balance of bone metabolism and hence closely related to bone metabolic diseases. To further explore the relationship between circadian rhythm and bone metabolism, the sleep deprivation model of zebrafish induced by continuous light and the MC3T3-EI cell model induced by Nr1d1-specific agonist STL1267 (STL1267) were used to study the intervention mechanism of liquiritigenin on bone metabolism imbalance mediated by circadian rhythm. Molecular docking, behavioral studies, calcein staining, alizarin red staining, alkaline phosphatase and osteocalcin activity, qRT-PCR, Western blotting, and other methods were adopted to screen and study the effects of licorice flavonoids on circadian rhythm disorder and its induced decrease of bone mineral density in zebrafish, osteogenic differentiation, and mineralization inhibition of MC3T3-EI cells. The results showed that liquiritigenin significantly alleviated the expression disorders of zebrafish circadian rhythm genes brain and muscle ARNT-like 1 (Bmal1), circadian locomotor output cycles kaput (Clock), period (Per), cryptochrome (Cry), retinoic acid receptor-related orphan receptor α (Rorα), and nuclear receptor subfamily 1 group D member (Nr1d1) induced by continuous light and caused zebrafish behavioral defects, decreased alkaline phosphatase and osteocalcin activity, and bone mineral density as well. Similarly, liquiritigenin effectively improved the expression of circadian rhythm-related genes at mRNA and protein levels in MC3T3-EI cells induced by STL1267 and enhanced cell viability, alkaline phosphatase and osteocalcin activity, and bone matrix mineralization. Therefore, this work reveals the key role of circadian rhythm in bone metabolism homeostasis, and proves that liquiritigenin can effectively alleviate the imbalance of bone homeostasis caused by circadian rhythm disorders, providing research basis for the application of natural small molecule components to improve circadian rhythm disorders and bone metabolism imbalance.
Targeting barrier integrity: Pseudoginsenoside RT2 ameliorates ulcerative colitis by driving epithelial renewal via the Wnt/β-catenin pathway.
Li Z, Tan L, Wu J … +8 more , Liu H, Geng X, Bu Y, Yue X, Wang Y, He X, Wang C, Liu J
Phytomedicine · 2026 Aug · PMID 42296875 · Publisher ↗
BACKGROUND: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by intestinal barrier dysfunction. Pseudoginsenoside RT2, an ocotillol-type ginsenoside widely present in Panax species...
BACKGROUND: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by intestinal barrier dysfunction. Pseudoginsenoside RT2, an ocotillol-type ginsenoside widely present in Panax species, possesses unexplored therapeutic potential for UC. PURPOSE: This study investigated the efficacy of RT2 against UC and its mechanisms of intestinal barrier protection by driving epithelial renewal. METHODS: Anti‑UC effects of RT2 were assessed in lipopolysaccharide (LPS)‑stimulated Caco‑2 cells and dextran sulfate sodium (DSS)‑induced mice. Integrated transcriptomic and proteomic analyses were performed to identify key pathways in barrier restoration. Mechanistic validation was conducted using DSS‑induced intestinal organoids (encompassing all epithelial lineages) and LPS‑stimulated IEC-6 cells (non-transformed intestinal epithelial model). Effects on Wnt/β-catenin pathway were assessed with inhibitor ICG-001. RESULTS: In Caco‑2 cells, RT2 restored transepithelial electrical resistance (TEER), regulated cytokines and upregulated tight junction proteins (TJs). In UC mice, RT2 dose‑dependently ameliorated disease activity index (DAI), improved colon length and histopathology, increased anti‑inflammatory cytokines and reduced pro‑inflammatory cytokines. RT2 enhanced TJs and epithelial markers. Multi-omics analysis linked RT2's benefits to Wnt/β-catenin pathway activation. In organoids, RT2 increased budding and Lgr5 expression. In IEC‑6 cells, RT2 restored TEER, promoted proliferation/migration, suppressed apoptosis and upregulated TJs and epithelial markers. Mechanistically, RT2 facilitated Wnt ligand-receptor binding, leading GSK-3β phosphorylation, disassembly of the destruction complex and β-catenin nuclear translocation. All effects were abolished by ICG‑001. CONCLUSIONS: RT2 attenuates UC by activating Wnt/β‑catenin pathway, thereby restoring intestinal barrier integrity via driving epithelial renewal, with efficacy comparable to the positive control drug SASP. RT2 represents a promising natural product candidate for UC treatment.
A sustained-release sinomenine hydrogel targets microglial ferroptosis via Nrf2-hmox1 activation to alleviate diabetic peripheral neuropathy.
Chen J, Zhu L, Chen Y … +5 more , Liu Y, Chen W, Liu X, Zhao P, Yang F
Phytomedicine · 2026 Aug · PMID 42287820 · Publisher ↗
BACKGROUND: Sinomenine (SIN), a bioactive alkaloid from Sinomenium acutum, possesses anti-inflammatory properties, but its efficacy against diabetic peripheral neuropathy (DPN) is limited by poor bioavailability and unde...
BACKGROUND: Sinomenine (SIN), a bioactive alkaloid from Sinomenium acutum, possesses anti-inflammatory properties, but its efficacy against diabetic peripheral neuropathy (DPN) is limited by poor bioavailability and undefined mechanisms. PURPOSE: This study aimed to evaluate the therapeutic effects and mechanism of a SIN-loaded hydrogel (Gel-SIN-M) in DPN. METHODS: Gel-SIN-M was engineered via crosslinking for controlled SIN delivery. DPN mice received perineural Gel-SIN-M injections. Pain thresholds (von Frey) and motor coordination (gait analysis) were quantified. Intraepidermal nerve fiber density (IENFD), toluidine blue staining, and TEM analyses were used to assess structural recovery. Molecular markers (Nrf2, Hmox1, GPX4, ACSL4) were analyzed by qPCR/Western blot. Ferroptosis inhibition was confirmed in high-glucose-stimulated microglia and further evaluated using RSL3 or ML385 intervention. RESULTS: Gel-SIN-M showed excellent biocompatibility and sustained drug release. Treatment significantly improved insulin levels, reduced blood glucose, and alleviated neuropathic pain and motor deficits in DPN mice. It decreased inflammation, restored neurite length, and enhanced nerve fiber density, axon diameter, and myelin thickness. Mechanistically, Gel-SIN-M upregulated Nrf2 and Hmox1, increased GPX4, reduced ACSL4 expression, and suppressed ferroptosis and Fe²⁺ accumulation in microglia. The Nrf2 inhibitor ML385 attenuated these protective effects, supporting the involvement of the Nrf2-Hmox1 axis. CONCLUSION: This study developed a thermosensitive Gel-SIN-M hydrogel that enables sustained, localized drug release in diabetic neuropathic lesions. Gel-SIN-M markedly alleviated neuropathic pain and motor dysfunction in DPN mice through activation of the Nrf2-Hmox1 axis and inhibiting microglial ferroptosis. Importantly, this work is the first to identify microglial ferroptosis as a novel pathogenic mechanism driving DPN progression, and it suggests activation of the Nrf2-Hmox1 axis as a potential multi-target therapeutic strategy integrating antioxidative, anti-inflammatory, and antiferroptotic effects. These findings introduce a new conceptual framework and a promising biomaterial-based approach for the treatment of DPN.
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