Search Results (354)

The discovery of ferroptosis and cuproptosis has significantly expanded the landscape of programmed cell death. Artesunate (ART), a semisynthetic derivative of artemisinin, exhibits pleiotropic pharmacological activities beyond its canonical antimalarial role, including anticancer and neuroprotective effects. However, a comprehensive review systematically integrating ART’s roles in modulating both ferroptosis and cuproptosis remains lacking. This review bridges this gap by synthesizing recent advances. The distinct core mechanisms of ferroptosis and cuproptosis are first outlined. Extensive evidence is then summarized regarding ART-induced ferroptosis in cancers, primarily through disrupting iron homeostasis (e.g., stabilizing transferrin receptor (TFRC), promoting ferritinophagy) and impairing antioxidant defenses (e.g., suppressing the System Xc⁻/ glutathione peroxidase 4 (GPX4) axis, targeting peroxiredoxins). In contrast, the anti-cuproptotic effect of ART is currently restricted to Parkinson’s disease (PD) models, mediated by the upregulation of astrocytic metallothionein 2A (MT2A) to chelate excess copper—the only validated cuproptosis-related mechanism of ART to date. The crosstalk between ferroptosis and cuproptosis at shared metabolic nodes, including glutathione depletion, mitochondrial dysfunction, and reactive oxygen species (ROS) amplification, is further delineated as a hypothesis-generating framework. This interplay suggests a theoretical potential for ART—when combined with functional nano-materials—to synchronously engage both death pathways, though direct experimental validation of such dual-pathway synergy for ART as a single agent remains lacking. Finally, translational prospects of ART in cancer therapy, neurodegenerative diseases, and hepatic fibrosis are discussed, together with current challenges and future directions. ART acts as a context-dependent modulator: pro-ferroptotic activity is evident across multiple disease models, whereas anti-cuproptotic activity is currently limited to PD and requires further validation. Systematic characterization of ART’s context-specific effects suggests a preclinical rationale for the future design of ART-based combination strategies targeting metal-dependent cell death, pending further validation. Full article

Background: Hypoxia-induced oxidative stress and ferroptosis contribute to blood–brain barrier dysfunction and neurovascular injury associated with ischemic stroke and neurodegenerative diseases. Luteolin, a naturally occurring flavonoid with potent antioxidant and anti-inflammatory activities, has emerged as a potential neuroprotective agent; however, its effects on hypoxia-induced ferroptosis in brain microvascular endothelial cells remain unclear. This study investigated the protective effects of luteolin and its association with changes in the PPARγ/FABP5/ALOX15 signaling pathway during hypoxia-induced ferroptotic injury. Methods: Human brain microvascular endothelial cells (HBEC-5i) were exposed to cobalt chloride (CoCl₂) to establish an in vitro hypoxia model and subsequently treated with luteolin. Cell viability was assessed using the MTT assay. Intracellular Fe²⁺ accumulation, reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH/GSSG) levels were determined using biochemical assays. The expression of ferroptosis- and hypoxia-related proteins, including GPX4, ALOX15, FABP5, PPARγ, HIF-1α, and VEGF, was evaluated by Western blotting. Results: CoCl₂-induced hypoxia significantly reduced cell viability and increased intracellular Fe²⁺ accumulation, ROS generation, lipid peroxidation, and ferroptosis-associated signaling in HBEC-5i cells. Hypoxic conditions upregulated ALOX15 and FABP5 expression while suppressing GPX4 and PPARγ levels. Luteolin treatment markedly attenuated these effects by restoring GSH/GSSG homeostasis, enhancing GPX4 expression, reducing ALOX15-mediated lipid peroxidation, and suppressing HIF-1α and VEGF expression. In addition, luteolin modulated the PPARγ/FABP5 signaling pathway, suggesting its involvement in the regulation of hypoxia-induced ferroptosis. Conclusions: Luteolin attenuates hypoxia-induced ferroptosis-associated changes in human brain microvascular endothelial cells by restoring redox homeostasis and is associated with coordinated modulation of the PPARγ/FABP5/ALOX15 pathway. These findings extend previous reports of the anti-ferroptotic effects of luteolin by providing evidence in brain microvascular endothelial cells under hypoxia-mimetic stress. Full article

Curcumin and natural curcuminoids possess numerous beneficial properties, including antioxidant, antitumor, and anti-inflammatory effects. However, their application is challenging because of instability and rapid metabolism. Cyclic C₅-curcuminoids, a subgroup of curcuminoids, are chemically more stable and less susceptible to hydrolysis or metabolism. In our study, seven synthetic compounds—five cyclic C₅-curcuminoids (compounds 8, 9, 11, 12, and 13) and two cyclic chalcones (compounds 4 and 5)—were examined using an in vitro 6-hydroxydopamine-induced neuronal damage model established with all-trans retinoic acid-differentiated SH-SY5Y and BV-2 microglial cells. The antioxidant, anti-apoptotic (including ferroptosis markers (iron, GSH/GSSG, and malondialdehyde)), apoptotic (PARP, cytochrome c, caspase 9, active caspase-3, and oligonucleosome release), and anti-inflammatory effects of these compounds were also investigated. Compounds 5, 9, 12, and 13 significantly decreased reactive oxygen species production (percentage changes: 5: 28.9%; 9: 32%; 12: 29.8%; 13: 49.2%) and increased antioxidant capacity (percentage changes: 5: 63.4%; 9: 85.8%; 12: 31.2%; 13: 85.9%) and antioxidant enzyme activity (catalase, superoxide dismutase, and glutathione peroxidase) in SH-SY5Y cells. Compounds 5, 9, and 12 decreased microglial activation by downregulating Iba1 expression (fold changes: 5: 0.73; 9: 0.39; 12: 0.33) and decreasing glutamate concentration (percentage changes: 5: 26.5%; 9: 41.2%; 12: 27.3%). Together with compound 13, they reduced pro-inflammatory cytokine (IL-6, TNFα) secretion and induced anti-inflammatory cytokine (IL-10) release in SH-SY5Y and BV-2 cells. Based on these results, the blood–brain barrier penetrations of compounds 5, 9, 12, and 13 were also investigated. The highest blood–brain barrier penetration was observed for compound 12 (P_app value 13.6 × 10⁻⁶ cm/s). Synthetic cyclic C₅-curcuminoids derived from curcumin overcome the limitations of stability and bioavailability and exhibit strong antioxidant, anti-inflammatory, and anti-apoptotic effects, making them promising candidates for treating neurodegenerative diseases. Full article

Metformin is a widely prescribed antidiabetic agent with pleiotropic effects extending beyond glycemic control, including anti-inflammatory and antioxidant actions. However, its impact on cytokine signaling and ferroptosis-related pathways in brown adipose tissue (BAT) remains poorly characterized. Here, we examined the transcriptional and metabolic responses to metformin in brown adipocytes and in a diet-induced obesity model. Differentiated brown adipocytes were treated with metformin and analyzed by RNA sequencing and RT-qPCR. C57BL/6 male mice fed a high-fat diet (HFD) were administered metformin to assess systemic metabolic parameters and BAT-specific responses, with validation by histology, RT-qPCR, and Western blot. Transcriptomic profiling identified differentially expressed genes enriched in cytokine–cytokine receptor interaction and ferroptosis-related KEGG pathways. Metformin modulated the expression of multiple inflammatory cytokine genes and upregulated antioxidant and ferroptosis defense-related genes, including the glutathione biosynthesis genes Gclc and Gclm, together with Hmox1, Gpx4, Nfe2l2 (Nrf2), and Slc7a11. Among these, Gpx4 showed the most consistent upregulation across mRNA and protein levels in BAT. In HFD-fed mice, metformin improved glucose tolerance and elevated the expression of antioxidant and ferroptosis-related genes in BAT, consistent with the in vitro findings. Together, these results indicate that metformin coordinately modulates antioxidant and ferroptosis defense-related gene expression in BAT, suggesting a tissue-protective transcriptional program under metabolic stress. Our findings identify candidate immunometabolic and ferroptosis-related targets of metformin in BAT and provide a basis for further mechanistic investigation of its tissue-specific actions beyond glycemic control. Full article

Myocardial infarction (MI) is characterized by sudden cardiomyocyte death due to impaired blood supply and remains a leading cause of mortality despite advances in management. Aloe vera, a plant rich in over 75 bioactive compounds, including vitamins, minerals, polysaccharides, and anthraquinones, has been widely used in traditional medicine and modern healthcare. Increasing evidence supports its cardioprotective potential through multiple mechanisms. Aloe vera and its derivatives have demonstrated antioxidative, anti-apoptotic, anti-inflammatory, antimicrobial, immunomodulatory, and vasodilatory effects relevant to MI pathophysiology. Compounds such as aloe-emodin, emodin, aloin, barbaloin, and selenium-enriched polysaccharides have been shown to modulate pathways including Nrf2/HO-1, TGF-β/SMAD, ERK, ferroptosis inhibition, ionic pump activity, and microRNA regulation. These molecular effects translate into reductions in oxidative damage, apoptotic signaling, inflammatory cytokine release, calcium imbalance, and creatine kinase/LDH leakage, while preserving myocardial structure and function in preclinical models. Collectively, preclinical studies suggest the potential cardioprotective effects of Aloe vera-derived preparations and compounds; however, robust clinical evidence in myocardial infarction is lacking, and their therapeutic relevance remains uncertain. Full article

Background: Small-cell lung cancer (SCLC) has a poor prognosis because of the development of drug resistance. Our previous studies showed that the plant steroid hormone, epibrassinolide (EB), interacts with human SCLC cells through inhibition of GSK3β-mediated signaling and overcomes drug resistance. However, the latter does not occur via membrane-mediated drug efflux, a commonly reported mechanism. Methods: We investigated a novel mechanism, ferroptosis, for drug resistance and the effects of EB. Pharmacological, cellular and molecular investigations were performed. We used drug-sensitive (NCI-H69) and multi-drug-resistant (VPA) SCLC cell lines. Results: 4-hydroxynonenal (HNE), a marker for lipid peroxidation and ferroptosis, was lower in drug-resistant VPA cells than drug-sensitive cells (H69) (22 vs. 60 pg/mg protein). Incubation with EB at a dose that reverses drug resistance in VPA cells increased HNE (94 pg/mg). Exogenously applied HNE increased intracellular HNE and reversed drug resistance (IC₅₀ for etoposide in VPA cells at 7.5 µM (untreated) vs. 1.0 µM (treated)). Ferrostatin, which inhibits ferroptosis, reduced HNE accumulation and increased drug resistance (IC₅₀ for etoposide at 5.5 µM (untreated) vs. 19 µM (treated)). As measured by phosphorylation, the signaling molecule Akt was more active in drug-resistant compared to drug-sensitive SCLC cells. This activation was accompanied by increased drug resistance. Both EB and a specific inhibitor of Akt phosphorylation/activation reversed this resistance. Akt activation was reflected in increased GSK3β activity. The latter was also inhibited by incubation in EB. The level of the GSK3β-controlled “antioxidant transcription factor” NRF2 was higher in drug-resistant VPA cells than drug-sensitive H69 cells. This increase was reversed in EB-treated cells. The protein level of the “antioxidant enzyme”, GPX4, which chemically reduces peroxidized lipids, was higher in VPA than H69 cells (21.2 vs. 10.1 pg/mg protein). Likewise, GPX4 enzyme activity was higher in drug-resistant than drug-sensitive cells. Incubation with EB reversed these increases. Incubation of SCLC cells with RSL3, a specific inhibitor of GPX4 activity, increased intracellular HNE and reversed drug resistance in VPA cells. Conclusions: These data indicate that ferroptosis is an important mechanism for drug resistance in SCLC cells and the plant steroid, EB, reverses drug resistance by interfering with the Akt signaling pathway and GPX4 anti-oxidant activity. Full article

Ferulic acid, a natural phenolic phytotherapeutic, which is mainly found in plant cell walls, has attracted the attention of researchers for its multiple pharmacological properties, especially for its anti-tumor potential. As an efficient antioxidant, the compound counteracts oxidative stress and modulates key molecular pathways involved in carcinogenesis. Recent studies demonstrate that ferulic acid exerts antiproliferative, pro-apoptotic, and anti-metastatic effects in various tumor models, including colon, breast, liver, and lung cancers. Mechanistically, ferulic acid affects components of prosurvival-signaling pathways such as PI3K/Akt, MAPK, and NF-κB, and stimulates programmed cell death by diverse mechanisms, including apoptosis, autophagy and ferroptosis. Furthermore, its ability to sensitize cancer cells to chemotherapeutic drugs with low toxicity to normal cells underscores its therapeutic potential. Despite promising preclinical anti-tumor activity, low water solubility and bioavailability limit its clinical use. For this reason, several attempts, ranging from chemical derivatives to nanodevices, have been made to improve ferulic bioavailability and anti-tumor efficacy. This review highlights the most significant and recent strategies to ameliorate the anticancer ability of ferulic acid in the perspective of a clinical application. Full article

Nonylphenol (NP), a typical emerging pollutant, is widely detected in water bodies, yet its hepatotoxic mechanisms and mitigation strategies remain underexplored. This study evaluated the protective effects of a mixed probiotic (Lactobacillus acidophilus and Bacillus subtilis) against NP-induced hepatotoxicity in Silurus meridionalis by integrating transcriptomic and metabolomic analyses, with validation by RT-qPCR and ELISA. The results showed that NP exposure disrupted the arachidonic acid (AA) pathway (activating pro-inflammatory COX and LOX pathways while the suppressing anti-inflammatory CYP450 branch), promoted ferroptosis via iron dyshomeostasis and oxidative damage, and impaired triglyceride (TG) synthesis. Probiotic pretreatment reversed these toxic effects by modulating AA metabolism, suppressing COX (ptgs2a↓ → PGE₂↓) and LOX (alox12↓ → MDA↓) pathways, while upregulating the CYP450 pathway (cyp2j↑ → 11,12-EET↑). Probiotics also enhanced Fe³⁺ sequestration (steap4↑) and antioxidant defense (CAT↑, gpx4a↑), limiting Fenton reaction-mediated oxidative injury, and restored hepatic TG synthesis through upregulation of the DHAP-to-TG cascade (DHAP—(gpd1b↑) → G3P↑—(gpat3↑) → LPA—(agpat6↑) → PA—(plpp7↑) → DAG↑—(dgat2↑) → TG↑). These findings suggest that NP induces hepatotoxicity in S. meridionalis, involving ferroptosis, AA metabolism disruption and impaired TG synthesis as interconnected pathological events. Probiotics likely counteract this toxicity through systemic metabolic reprogramming. Collectively, these findings elucidate the hepatotoxic mechanisms of NP in S. meridionalis and offer toxicological data for its risk assessment, supporting the potential of probiotic-based strategies to mitigate emerging pollutant impacts in aquatic organisms. Full article

Given the growing demand for health-promoting foods, there is increasing interest in the multi-dimensional regulatory effects and the mechanisms of food-derived bioactives. Here, we report that KSVSPKFLTG, an anti-inflammatory peptide from Magallana gigas with ACE2-binding properties, protects SHSY-5Y cells against MPP⁺/FAC-induced neurotoxicity. The peptide attenuates oxidative stress damage in SHSY-5Y cells and improves the mitochondrial membrane potential. It also mitigates iron overload and upregulates ferroptosis-related protective proteins (GPX4, SLC7A11, BCBP2, SLC40A1) via activating the renin–angiotensin system. These findings reveal an RAS-modulating neuroprotective mechanism of the oyster-derived anti-inflammatory peptide, simultaneously opening new avenues for alleviating nerve damage caused by inflammation through bioactive peptides. Full article

Background/Objectives: Sodium butyrate, a short-chain fatty acid produced by gut microbial fermentation of dietary fiber, has attracted increasing interest as a potential adjunctive therapy for ulcerative colitis (UC) because of its anti-inflammatory, barrier-protective, and immunomodulatory properties. This systematic review aimed to evaluate the current clinical and preclinical evidence regarding the efficacy and mechanisms of sodium butyrate in UC. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines and registered in PROSPERO (CRD420261437741). PubMed/MEDLINE, Scopus, Web of Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from February through April 2026. Eligible clinical and experimental studies investigating oral or rectal administration of sodium butyrate in UC or experimental colitis were included. Risk of bias was assessed using RoB 2, ROBINS-I, or the SYRCLE tool according to study design. Results: Twenty-two studies were included, comprising ten clinical trials, one prospective observational study and eleven preclinical animal studies. In adults diagnosed with UC, oral sodium butyrate, particularly microencapsulated formulations, demonstrated encouraging effects as an adjunct to standard therapy by improving clinical remission rates, quality of life and reducing disease activity and inflammatory biomarkers. Evidence in pediatric inflammatory bowel disease remained inconsistent. Studies evaluating rectal sodium butyrate enemas reported variable clinical efficacy despite evidence of local biological activity. Preclinical studies consistently demonstrated reduced intestinal inflammation, improved epithelial barrier integrity, modulation of oxidative stress, favorable alterations of the gut microbiota, and regulation of several mechanistic pathways identified across individual preclinical studies, including PI3K/AKT/mTOR, WNT/ERK, ERK/STAT3, autophagy and ferroptosis. Conclusions: Current evidence suggests that sodium butyrate represents a promising adjunctive therapeutic strategy for UC, supported by consistent mechanistic findings and encouraging clinical results, particularly with oral formulations. However, the available clinical evidence remains heterogeneous, and larger, well-designed randomized controlled trials with standardized formulations and treatment protocols are required before its routine clinical implementation can be considered. Full article

Objectives: Renal ischemia–reperfusion (I/R) injury is one of the most important pathological triggers of acute kidney injury. This study aimed to investigate the protective effects of meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, against renal I/R injury through specific cell death pathways including inflammation, apoptosis, necroptosis, and the MAPK/ERK pathway, which is potentially linked to regulated cell death mechanisms such as ferroptosis. Methods: Male Wistar Albino rats weighing 280–300 g were used in the study and were divided into four groups: Sham, IR (40 min ischemia + 120 min reperfusion), Meloxicam + IR, and Meloxicam + IR1. Bilateral renal ischemia was induced for 40 min via a retroperitoneal approach under anesthesia. Meloxicam was administered intravenously at a dose of 1 mg/kg at the initiation of reperfusion in the Meloxicam + IR group, whereas in the Meloxicam + IR1 group, the same dose was administered 1 h after the onset of reperfusion. Total reperfusion time was 120 min in both groups. Renal function parameters (BUN and creatinine) and oxidative stress markers (TAS and TOS) were measured. Inflammatory cytokines (IL-6, IL-1β, and IL-10), the glomerular filtration injury marker Cystatin C, the tubular injury marker KIM-1, the apoptotic marker Caspase 3, the necroptosis markers RIPK3 and MLKL, and MAPK signaling pathway alterations (ERK1/2 and pERK1/2 levels) associated with cellular survival and death signaling were evaluated. Results: Most notably, meloxicam markedly modulated apoptosis, the expression of necroptosis markers RIPK3 and MLKL, and the activation of pERK1/2, a key node in MAPK signaling that is regulatory in cell survival and cell death processes. The drug also suppressed pro-inflammatory cytokines (IL-6 and IL-1β) while preserving anti-inflammatory IL-10 levels. Furthermore, improvements were observed in the levels of KIM-1, a marker of tubular injury, and Cystatin C, a marker of glomerular filtration impairment. Consequently, meloxicam administration significantly reduced the elevated serum creatinine and TOS levels observed in the IR group, although serum BUN levels remained without notable alteration. Conclusions: The findings of this study suggest that meloxicam may extend beyond its role as a classical anti-inflammatory agent, potentially offering biochemical and functional protection against renal I/R injury in association with the modulation of specific cell death mechanisms, including necroptosis and apoptosis, as well as the MAPK signaling pathway. Full article

The continued rise in fishmeal prices and the scarcity of fishery resources have led to an increase in the use of plant-based protein sources in compound feed, making mold contamination in compound feed a frequent occurrence. Aflatoxin B1 (AFB1) contamination in aquaculture feed can seriously harm fish growth and liver health; it is extremely toxic, posing an even greater risk to carnivorous fish such as grouper. Lycopene, a natural carotenoid, has antioxidant and anti-inflammatory physiological functions and may act as a functional feed additive to mitigate damage induced by mycotoxins. This study utilized hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) as the experimental model. An 8-week feeding trial was performed to systematically assess the impact of lycopene supplementation at levels of 0, 200, 400, 600, and 800 mg/kg to a basal diet containing 800 μg/kg AFB1 on the fish’s growth performance, antioxidant capacity, liver health, inflammation-related gene expression, and hepatic transcriptome. The results showed that adding 200 mg/kg lycopene to the feed significantly increased the FWB and SGR (p < 0.05) of hybrid grouper. An appropriate amount of lycopene could enhance the antioxidant capacity of serum and liver, significantly increase the activities of catalase (CAT) and superoxide dismutase (SOD), and significantly decrease serum alanine aminotransferase (ALT) activity while increasing albumin (ALB) levels (p < 0.05). An amount of 200 mg/kg lycopene significantly alleviated AFB1-induced hepatocyte vacuolation, steatosis, and inflammatory cell infiltration, while the protective effect of higher doses was weakened. The gene expression results showed that 200 mg/kg lycopene significantly upregulated the expression of antioxidant-related genes such as cat, sod, and nrf-2, and increased the expression level of the anti-inflammatory factor il10 (p < 0.05). The transcriptome analysis identified a total of 621 differentially expressed genes, which were mainly enriched in metabolic pathways, fatty acid metabolism, PPAR signaling pathway, redox process, ferroptosis, NF-κB signaling pathway, and Toll-like receptor signaling pathway. In summary, the addition of 200 mg/kg lycopene to the feed can effectively alleviate the growth inhibition and liver damage caused by AFB1 in hybrid grouper. Its mechanism of action may be related to enhancing antioxidant defenses, improving liver tissue structure, regulating lipid metabolism, and maintaining immune homeostasis. The research results indicate that lycopene can be used as a natural functional feed additive to alleviate AFB1 toxicity in hybrid grouper aquaculture. Full article

Osteosarcoma is a common malignant bone tissue tumour that frequently occurs in the adolescent population, with recurrence and metastasis rates that remain high under current treatment strategies, necessitating the development of cost-effective and efficient anti-osteosarcoma drugs. Sanguinarine, a benzophenanthridine alkaloid derived from plants in the Papaveraceae family, possesses anti-tumour capabilities; however, its clinical application is limited due to poor water solubility and potential organ toxicity. Through screening 30 sanguinarine analogues, in this study we found that analogue 25 exhibited significant activity and could suppress cell proliferation and arrest the cell cycle at the G0/G1 phase in U2OS and MG63 cells, with IC₅₀ values of 1.484 and 1.954 μM, respectively. Analogue 25 could also induce cell apoptosis by increasing the levels of cleaved caspase-9 and BAX. Subsequently, we demonstrated that analogue 25 increased the ROS level, decreased the mitochondrial membrane potential, and increased lipid peroxidation in osteosarcoma cells. After reducing ROS levels through NAC, analogue 25 was able to regulate mitochondrial-mediated osteosarcoma cell apoptosis by modulating the ROS level. Furthermore, analogue 25 could also regulate the expression of ferroptosis-related proteins (including GPX4, SLC7A11 and PTGS2) through the NRF2/GPX4 pathway, ultimately leading to the accumulation of lipid peroxidation and ferroptosis. In a xenograft mouse tumour model derived from osteosarcoma cell lines, analogue 25 exhibited stronger anti-tumour activity than sanguinarine by regulating apoptosis and ferroptosis without causing liver or kidney toxicity. These findings highlight that sanguinarine analogue 25 has beneficial effects in treating osteosarcoma. Full article

Mammary gland inflammation, clinically expressed as mastitis in dairy ruminants and lactating women, arises from a self-amplifying loop of pathogen sensing, oxidative stress and innate immune activation, and remains a leading driver of antibiotic use, milk-quality loss and morbidity. Mounting pressure to reduce antimicrobial dependence has refocused attention on flavonoids—structurally diverse plant polyphenols with multi-target bioactivity, derived mainly from in vitro and rodent mastitis models. This review integrates contemporary evidence on the six principal flavonoid subclasses within a unifying molecular framework. Across subclasses, flavonoids converge on shared targets: the TLR4–MyD88–NF-κB axis, MAPK cascades, the Keap1–Nrf2–ARE antioxidant pathway, the NLRP3 inflammasome and tight-junction proteins of the blood–milk barrier. Less canonical mechanisms—m⁶A epitranscriptomic regulation, ferroptosis suppression, AhR signalling, anti-virulence binding to bacterial enzymes such as IGPD, and gut-microbiota-driven remodelling of the gut–mammary axis—expand the pharmacological landscape. We additionally appraise the subclasses comparatively, identifying flavanones and the flavone baicalin as carrying the strongest translational evidence, and examine the conflicting findings, model limitations, and delivery, residue and regulatory barriers that currently separate mechanistic promise from on-farm application. We outline structure–activity considerations and translational priorities, and position flavonoids as mechanism-rich, antibiotic-sparing candidates for the prevention and adjunctive management of mammary gland inflammation in dairy ruminants. Full article

Alzheimer’s disease (AD) is a complex, multifactorial neurodegenerative disorder whose core pathological hallmarks include Aβ aggregation, tau hyperphosphorylation, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota dysbiosis. Lignans, a class of naturally occurring polyphenolic dimers widely distributed in medicinal plants and diet, exhibit multi-target neuroprotective effects with low toxicity. This review provides a systematic synthesis of the anti-AD pharmacological mechanisms underlying nine structurally distinct lignan subtypes—dibenzocyclooctadiene, tetrahydrofuran, bisepoxy, benzofuran, and biphenyl types—emphasizing scaffold-dependent structure–activity relationships. Key mechanistic pathways encompass direct inhibition of Aβ aggregation and tau phosphorylation, activation of the Nrf2 antioxidant signaling axis and PI3K/Akt pro-survival pathways, suppression of NF-κB-mediated neuroinflammation, restoration of cholinergic function, protection of mitochondria via SIRT3, inhibition of ferroptosis through Gsk3β/Nrf2/GPX4 signaling, and modulation of the gut–brain axis via microbiota-mediated conversion to enterolactone. This review addresses key pharmacokinetic limitations such as low oral bioavailability, rapid metabolism, and limited brain exposure, alongside strategies including structural modification, brain-targeted delivery systems, and gut microbiota modulation. Despite promising preclinical evidence, clinical translation remains limited. Future research priorities should focus on direct target validation, network pharmacology, optimized formulations, and well-designed clinical trials to develop lignans into next-generation anti-aging and anti-AD therapeutics. Full article