Research Highlights

Spinal cord injury (SCI) is a debilitating condition associated with significant morbidity and permanent disability. The neuroprotective potential of deferoxamine (DFO) in SCI by targeting ferroptosis has been highlighted; however, the underlying molecular mechanisms remain elusive. The present study aimed to investigate the role of the Nrf2/heme oxygenase‑1 (HO‑1) signaling pathway in mediating the inhibitory effects of DFO on neuronal ferroptosis following SCI. The study commenced with a bioinformatics analysis of the SCI microarray dataset, GSE162610. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated significant activation of ferroptosis following SCI, while Gene Ontology analysis revealed that oxidative stress, inflammatory response and glutathione peroxidase activity were key biological processes associated with ferroptosis post‑SCI. The Nrf2, glutathione peroxidase 4 (GPX4), HO‑1 (encoded by Hmox1) and xCT (encoded by Slc7a11) genes were selected for further investigation. Subsequent experiments employed the Nrf2‑specific inhibitor ML385 to evaluate the regulatory role of the Nrf2/HO‑1 pathway. In vitro, an erastin‑induced neuronal ferroptosis model was established using ventral spinal cord 4.1 cells, while in vivo, a spinal cord contusion model was constructed using C57BL/6J mice for behavioral, histopathological and immunological assessments. The results demonstrated that, compared with the SCI group, DFO treatment significantly upregulated the expression of Nrf2, HO‑1, xCT and GPX4 both in vitro and in vivo as well as attenuated neuronal loss and tissue damage and promoted motor functional recovery in mice. Conversely, the administration of ML385 largely reversed these molecular and functional effects of DFO, thereby diminishing its neuroprotective efficacy. These findings indicated that DFO alleviated neuronal ferroptosis and promoted functional recovery after SCI, at least in part, through activation of the Nrf2/HO‑1 signaling pathway and enhancement of the xCT/GPX4 antioxidant system. Therefore, the present study elucidated the involvement of the Nrf2/HO‑1 signaling pathway in mediating the neuroprotective effects of DFO in SCI, highlighting the therapeutic potential of DFO and providing a theoretical foundation for future targeted strategies against ferroptosis in SCI management.

Cardiovascular complications associated with type 2 diabetes mellitus (T2DM) pose a serious threat to human health. Folic acid deficiency is associated with various diseases, including atherosclerosis. However, it remains unclear whether folic acid has a protective effect on vascular injury induced by T2DM. To address this, folic acid was administered to db/db or db/dm mice, and endothelial cells were treated under high-fat and high-glucose (HGF) conditions to evaluate the effect of folic acid on cell viability. RNA sequencing was performed to explore the potential targets of folic acid. The results indicated that folic acid alleviates endothelial cell injury and ferroptosis in T2DM by upregulating the SIRT6/NRF2 pathway and mitigating oxidative stress, Fe2+ accumulation and lipid peroxidation. The SIRT6 inhibitor counteracted the protective effect of folic acid on endothelial cells in vitro. Overall, folic acid may be a promising drug for treating or alleviating endothelial dysfunction in T2DM.

Anti-inflammatory peptides (AIPs), a class of biologically active molecules with high specificity and low toxicity, demonstrate outstanding potential in replacing traditional anti-inflammatory drugs. In this review, the multiple natural sources of AIPs (including marine organisms, terrestrial plants and animals, and microorganisms) are comprehensively reviewed, and their core molecular mechanisms to inhibit inflammatory responses through the synergistic regulation of key signaling pathways such as NF-κB, MAPK, PI3K/Akt, JAK/STAT, and Keap1-Nrf2 are examined. To address the bioavailability bottlenecks of AIPs' oral delivery, such as gastrointestinal degradation and low intestinal permeability, this review systematically analyzes the mechanisms of action of enhancement strategies, including nanocarrier technologies and chemical modification methods. Finally, we propose cutting-edge future directions such as artificial intelligence-guided design and innovative combination therapies to accelerate their clinical translation. This work provides not only a solid theoretical foundation but also practical insights for the development of AIPs as next-generation anti-inflammatory ingredients.

Osteoporosis (OP) is a common metabolic bone condition characterized by the breakdown of bone microarchitecture and a reduction in bone mass, which notably heightens the likelihood of fracture, especially among older adults. Currently, therapeutic strategies for OP include antiresorptive and anabolic drugs. However, these treatments are often associated with adverse effects such as an increased risk of osteosarcoma, cardiovascular complications, and atypical fractures. This has led to an increased focus on alternative therapies, particularly those derived from traditional Chinese medicine (TCM). Natural coumarins (NC), which are naturally occurring compounds from various plants, have shown promise in modulating bone metabolism by controlling the function of osteoblasts and osteoclasts. Representative compounds such as osthole, psoralen, isopsoralen, and fraxin have demonstrated strong anti-osteoporotic potential through distinct mechanisms: osthole enhances osteoblast differentiation via the Wnt/β-catenin and BMP2 pathways; psoralen activates estrogen receptor α signaling to promote osteogenesis and inhibit osteoclastogenesis; isopsoralen alleviates oxidative stress to support osteogenic gene expression; and fraxin suppresses osteoclast formation by inhibiting ROS/NF-κB while promoting osteoblast-mediated bone formation through the Nrf2/GPX4 pathway. Collectively, these findings highlight that NC exert multifaceted effects on bone metabolism by regulating classic pathways (OPG/RANKL/RANK, Wnt/β-catenin, BMP/Smad, NF-κB, MAPK, and estrogen signaling) as well as cellular processes such as oxidative stress, autophagy, apoptosis, and adipogenesis. By synthesizing the current body of research, this review underscores the therapeutic potential of NC and encourages further innovation in OP treatment strategies.

5-Fluorouracil (5-FU) is widely used in the treatment of various solid tumors; however, its clinical use is often limited by hepatotoxicity. Boldine, an aporphine alkaloid, has been reported to possess antioxidant, anti-inflammatory, and hepatoprotective properties. The present study evaluated the hepatoprotective potential of boldine against 5-FU-induced liver injury in Wistar rats. Hepatotoxicity was induced by a single intraperitoneal injection of 5-FU (150 mg/kg). Following 5-FU administration, rats were orally treated with boldine (10 or 20 mg/kg body weight) or the standard hepatoprotective agent silymarin (100 mg/kg body weight) once daily for 7 days. At the end of the experimental period, serum transaminases, oxidative stress markers, antioxidant status, and hepatic gene expression related to oxidative stress and inflammation were evaluated using PCR analysis. Administration of 5-FU was associated with increased serum transaminases and oxidative stress markers, consistent with hepatocellular injury. In addition, 5-FU exposure was accompanied by reduced mRNA expression of antioxidant-related genes (Nrf2, NQO1, and HO-1) and increased expression of CUL3 and inflammatory/apoptosis-related markers (ASK1, ERK1, and NF-κB), along with decreased Bcl-2 expression. Boldine treatment significantly attenuated biochemical and molecular alterations, enhanced dihydropyrimidine dehydrogenase expression involved in 5-FU metabolism, and ameliorated histopathological changes. Overall, these findings suggest that boldine may exert hepatoprotective effects against 5-FU-induced liver injury, potentially through modulation of oxidative stress and inflammatory pathways.

BACKGROUND: Acrylamide (ACR), an environmental neurotoxicant prevalent in thermally processed foods, contributes to brain injury via oxidative stress and neuroinflammation. The cumulative effects of long-term low-dose exposure are particularly alarming. As a traditional food ingredient, the inflorescence of Coreopsis tinctoria Nutt. is rich in polyphenolic compounds that exhibit significant anti-inflammatory and antioxidant properties. This study systematically evaluated the neuroprotective potential of Coreopsis tinctoria Nutt. polyphenols (CTNP) against chronic low-dose ACR exposure in mice. RESULTS: Behavioral analyses demonstrated that CTNP (0.25-1.00 g kg-1) significantly ameliorated ACR-induced gait abnormalities and restored voluntary activity. CTNP mitigated neuronal misalignment and loss of synaptic density in the hippocampal CA1/CA3 regions and markedly reduced serum levels of brain injury markers MBP and GFAP by 30.6% and 41.7%, respectively. Mechanistic investigations revealed that CTNP attenuated oxidative damage via activation of the Nrf2/HO-1 pathway, leading to decreased brain reactive oxygen species and malondialdehyde levels while enhancing catalase, superoxide dismutase and glutathione peroxidase activities. Furthermore, CTNP suppressed MAPK pathway-mediated neuroinflammation, reducing pro-inflammatory factors such as COX-2, TNF-α and IL-1β. CONCLUSION: These findings demonstrate that CTNP, as diet-derived bioactives, mitigate ACR neurotoxicity through coordinated modulation of Nrf2/HO-1 antioxidant and MAPK anti-inflammatory pathways, supporting their potential as a functional food component for preventing environmental toxicant-associated neural damage. © 2026 Society of Chemical Industry.

Uveitis is a leading cause of vision loss in the working-age population, yet conventional hormone therapy often comes with numerous side effects. Here, we present a noninvasive topical treatment strategy using HSCDs─a bioactive carbon dot derived from plant-based components─as eye drops for autoimmune uveitis. We developed these carbon dots with strong scavenging capacity against reactive oxygen and nitrogen species (RONS) and the ability to penetrate from the ocular surface into the retina. In an experimental autoimmune uveitis (EAU) mouse model, this treatment demonstrated dual-pronged therapeutic effects by alleviating oxidative stress, inhibiting microglial M1 activation via the Nrf2/HO-1 pathway, and reducing the inflammatory reactivity of retinal vascular endothelial cells, while restoring retinal vascular homeostasis, thereby ameliorating uveitis. Additionally, a biosafety assessment confirmed that HSCDs possess favorable biocompatibility and immunological safety. Collectively, our work establishes these carbon dots as a safe and effective topical nanotherapeutic for autoimmune uveitis.

Atherosclerotic plaque instability is a direct cause of cardiovascular and cerebrovascular events. In this study, a mitochondria-targeted liposome (LIP), modified with triphenylphosphonium (TPP) to enable specific mitochondrial delivery, was innovatively constructed to encapsulate a PCSK9 inhibitor (TPP-LIP@PCSK9). The aim was to explore a novel strategy for stabilizing plaques by restoring mitochondrial function in endothelial cells. Characterization results showed that TPP-LIP@PCSK9 possesses favorable nano-characteristics, and its targeting capability was confirmed through mitochondrial co-localization experiments. In an Apoe-/- mouse model, TPP-LIP@PCSK9 treatment significantly inhibited carotid artery plaque progression and reduced oxidative damage within the plaques. It markedly enhanced the activity of antioxidant enzymes (T-SOD, CAT) and decreased the level of lipid peroxidation products (MDA) in plaque tissue. Further analysis by Western blot and transcriptomics revealed that TPP-LIP@PCSK9 downregulated the mitochondrial damage marker proteins PINK1/Parkin, activated the Nrf2/UCP2-mediated antioxidant pathway, and modulated signaling pathways closely associated with oxidative stress and metabolism. This study is the first to report the direct role of PCSK9 in mitochondrial oxidative damage within plaque endothelial cells and to achieve effective intervention via nanotechnology, providing a new perspective for the treatment of atherosclerosis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by sustained oxidative stress, inflammation, and epithelial damage. The transcription factor Nrf2 is a master regulator of antioxidant and cytoprotective defenses, and its dysregulation has been implicated in COPD pathogenesis. METHODS: We first investigated Nrf2 expression and its downstream antioxidant genes in lung tissue and neutrophils from healthy donors and COPD patients, and examined their association with disease severity (GOLD stage). We then compared the efficacy of two mechanistically distinct Nrf2 activators-omaveloxolone (an electrophilic compound) and LAS200813 (a peptide-based Keap1-Nrf2 protein-protein interaction inhibitor)-using bardoxolone methyl as a high-potency reference. Functional analyses were performed in human bronchial epithelial cells (HBECs) and peripheral blood neutrophils from both groups. RESULTS: Nrf2 and target gene expression were significantly reduced in COPD samples and correlated with disease severity, indicating pathway dysfunction. Pharmacological activation promoted Nrf2 nuclear translocation, restored redox balance, increased intracellular glutathione, and reduced ROS levels in epithelial and immune cells. Both activators induced HO-1 and NQO1 expression and attenuated cigarette smoke extract-induced release of IL-8, MMP-9, and IL-6, including in COPD-derived cells. In bronchial epithelial cells, Nrf2 activation was also associated with a reduction in CSE-induced apoptosis. Omaveloxolone showed slightly higher potency, while LAS200813 displayed comparable functional efficacy. CONCLUSION: These results confirm that the Nrf2 pathway is compromised in COPD and support selective Nrf2 activation-particularly via peptide-based approaches-as a promising therapeutic strategy to mitigate oxidative and inflammatory injury in the disease.

L-theanine (Thea), a non-protein amino acid derived from Camellia sinensis (green tea) has emerged as a promising nutraceutical for the prevention and treatment of cardiovascular diseases (CVDs) and their comorbidities, thanks to its favorable safety profile, oral bioavailability, and natural origin. While extensive literature exists on green tea polyphenols, this review provides the first comprehensive synthesis of Thea's protective functions in specific cardiovascular contexts: attenuation of myocardial ischemia/reperfusion injury and heart failure, reduction of blood pressure, improvement of the lipid profile, inhibition of atherosclerotic plaque formation, promotion of adipose tissue browning, and modulation of glucose metabolism. This review also details the current evidence on Thea's cardioprotective mechanisms, with particular attention to its modulation of oxidative stress, inflammation, and apoptosis. We examined its regulatory effects on key molecular targets, including transcription factors such as Nrf2, PPARα, PPARγ, and NF-κB, as well as proteins involve in mitochondrial integrity (BCL-2, BAX), and metabolic homeostasis (AMPK, SREBP-1c, eNOS). Furthermore, this review advances the field by integrating pharmacokinetic data, safety assessments, recent advances in delivery systems, such as nanoencapsulation and co-formulation strategies, and connects mechanistic insights from preclinical models with potential clinical applications. We also identify critical gaps in research, such as the need for studies in chronic disease models, dose optimization, and evaluation in complex conditions like hypertrophic and dilated cardiomyopathy. Given the growing preclinical evidence and pending clinical validation, Thea represents a natural and compelling candidate for comprehensive cardiovascular prevention and treatment strategies.

Oxidative stress play key roles in the pathogenesis of bronchopulmonary dysplasia (BPD). MOTS-c is a mitochondria-derived peptide containing 16 amino acids that is reported to be involved in the treatment of oxidative stress-related diseases. However, whether MOTS-c functions on hyperoxia-induced BPD remains unknown. The purpose of this study was to investigate the potential therapeutic effect and mechanism of MOTS-c on hyperoxia-induced BPD. Here, hyperoxia (70% O2) was used to mimic the murine BPD model. We found that MOTS-c content was reduced in hyperoxia-induced BPD mice. Exogenous MOTS-c supplementation alleviated growth retardation, attenuated alveolar simplification, and pulmonary vascular abnormalities in hyperoxia-induced BPD mice. Besides, MOTS-c supplement increased cell viability, inhibited cell death and promoted tube formation in hyperoxia-stimulated HUVECs. Moreover, MOTS-c administration significantly inhibited inflammation and oxidative stress both in vivo and in vitro. In addition, the beneficial effect of MOTS-c was Nrf2 dependent, since the anti-inflammation, anti-oxidative and pro-angiogenic effects of MOTS-c were offset in ML385 (a specific Nrf2 inhibitor) treated HUVECs or in Nrf2 deficiency mice. In conclusion, MOTS-c protects against hyperoxia-induced lung alveolar simplification and abnormal angiogenesis in an Nrf2-dependent manner. MOTS-c emerges as a potential anti-oxidant therapeutic agent to treat hyperoxia-induced BPD.

Phytochemicals are naturally occurring bioactive compounds found in plant seeds. These bioactive substances have attracted considerable attention for their proven potential to modulate oxidative stress and prevent cancer. Seeds are abundant in phenolics, flavonoids, terpenoids, chlorophylls, organosulfur compounds, and other important constituents, exhibited their potential as a strong antioxidant that can efficiently neutralize reactive oxygen species. By controlling lipid peroxidation and enhancing cellular resilience, antioxidants present in seeds maintain cellular redox balance, contribute to immunological modulation, and activate critical signaling pathways, including the Nrf2/Keap 1 and NF-κB signaling pathway, which governs the expression of proteins having antioxidant potential. Phytochemicals also exhibit strong anticancer properties by inducing apoptosis in cancerous cells while safeguarding healthy cells and tissues. The review emphasizes the potential of phytochemicals as selective growth inhibitors, endorsing their role as functional foods in various nutrition therapies. Beyond biological effects, nanotechnology has improved stability, solubility, and targeted delivery of phytochemicals, significantly enhanced their therapeutic potential. AI-driven approaches and omics technology has revolutionized the phytochemical discovery, formulation, and personalized applications. This review highlights the recent evidence from in vitro, in vivo, and clinical studies, alongside the translational relevance of phytochemicals in food and pharmaceutical industries. By merging molecular insights with technological advancements, this review explores the potential of phytochemicals in preventive and therapeutic strategies against chronic diseases. Future research should focus on personalized delivery systems, human efficacy, and harmonization to maximize their real-world impacts.

BACKGROUND: Asthma is a disease that still lacks effective preventive measures with distinctive pathologicfeatures, particularly inflammation, oxidative stress, apoptosis and endoplasmic reticulum (ER) stress. 4-Octyl itaconate (4-OI) has been reported to possess immunomodulatory, anti-inflammatory and antioxidant properties. METHODS: In this study, we evaluated the efficacy of 4-OI in airway inflammation and oxidative lung injury in asthmatic mice exposed to PM2.5 using the ovalbumin (OVA)+ PM2.5-induced asthma model in BALB/c mice. In addition, we further evaluated the role of 4-OI in protecting BEAS-2B cells from PM2.5 induction using an in vitro model of asthma. RESULTS: The results showed that 4-OI attenuated airway inflammatory cell infiltration and the levels of mouse whole lung lavage fluid inflammatory factors, and decreased the levels of MDA and ROS, while increasing the activity of SOD. Meanwhile, in in vitro experiments, it was further demonstrated that 4-OI transcriptionally regulated MFN2 via Nrf2, which reduced the intracellular and mitochondrial ROS content, and the fluorescence intensities of Mito Tracker Red+ calnexin+ and MFN2+PERK+ were also significantly reduced. Fluo-3 AM experiment showed that 4-OI reduced Ca2+ concentration by regulating MFN2 through Nrf2 transcription. In addition, the protein expression of MFN1, MFN2, Bcl-2, and pro-Caspase3 was significantly elevated and that of PERK, GRP78, CHOP, Caspase12, Bax, and cleaved-Caspase3 was significantly decreased by Western Blot. CONCLUSIONS: In summary, our research demonstrated found that 4-OI improved the dysfunction of mitochondria-associated endoplasmic reticulum membranes by modulating MFN2 via Nrf2 transcription, thereby reducing the inflammatory response in asthmatic airways during early exposure to PM2.5.

Paclitaxel (PTX) is a potent taxane widely used in the treatment of solid tumors and can cause dose-limiting peripheral neuropathy. This study evaluated the therapeutic potential of selenium in a paclitaxel-induced peripheral neuropathy model. A total of 30 male Sprague-Dawley rats were divided into five groups (n=6): Control, SE1, PTX, PTX+SE0.5, and PTX+SE1. PTX (2mg/kg, i.p., days 1-5) was administered followed by SE (0.5 or 1mg/kg, i.g., days 6-15); sciatic nerve tissues were analyzed on day 16. In addition to molecular and histopathological analyses, behavioral assessments were performed to evaluate mechanical nociception, locomotor activity, and anxiety-like behavior. PTX significantly reduced mechanical pain threshold, impaired locomotor performance, and decreased exploratory behavior. At the molecular level, PTX increased oxidative stress by elevating MDA levels while decreasing SOD and GSH; it also increased TNF-α, IL-1β, and IL-6, and reduced IL-10 levels. Histopathologically, marked axonal degeneration and demyelination, along with reduced myelin fiber area, were observed. SE treatment, particularly at 1mg/kg, restored mechanical pain threshold, improved locomotor parameters, and attenuated anxiety-like behavior. SE also brought oxidative stress markers closer to control levels, suppressed pro-inflammatory cytokines, increased IL-10, reduced histopathological damage, and improved myelin integrity. Immunostaining revealed that SE attenuated PTX-induced increases in BAX, caspase-3, and 8-OHdG, while partially reversing the decrease in Bcl-2. In qPCR analyses, PTX decreased BDNF and increased GFAP expression, which were normalized by SE. SE suppressed the PTX-induced increase in Keap-1 and enhanced Nrf-2 expression. In addition, SE treatment partially restored HO-1 expression, with statistically significant increases observed compared to the PTX group, although levels did not fully return to control values.

Escherichia coli (E. coli), a gram-negative bacterium typically found in the gastrointestinal tract, encompasses pathogenic strains that can lead to serious infections such as foodborne illnesses, sepsis, and urinary tract infections. The interaction between E. coli and immune cells, especially macrophages and T lymphocytes, is crucial for bacterial survival and evasion of the immune response. In this research, we utilized an in vitro co-culture model involving primary murine splenic macrophages and T cells to explore the contribution of different cytokines on autophagy, apoptosis, and phagocytic activity during E. coli infection. The cytokine administered included IFN-γ, IL-12, IL-4, IL-10, and their combinations. Flow cytometric analysis indicated a consistent increase in the proportion of macrophages compared to lymphocytes across all cytokine treatment conditions. Regarding the macrophage signalling pathway, IFN-γ+IL-12 fostered a proinflammatory environment characterized by a cytokine amplification loop and heightened ROS levels, which enhanced apoptosis and disrupted autophagy, as demonstrated by increased cleaved caspase-3 and decreased LC3-II and Beclin1 expression. Conversely, IL-4+ IL-10 facilitated an anti-inflammatory phenotype, leading to suppressed IL-12 production, lowered ROS levels, enhanced STAT3 and Nrf2 signalling, and a restoration of autophagic flux. Importantly, co-stimulation with IFN-γ and IL-4 resulted in conflicting signalling, where IL-4 alone was inadequate to mitigate the autophagy impairment caused by IFN-γ. These results underscore how varying cytokine environments influence macrophage functionality during E. coli infection, particularly by modulating the interplay between apoptosis and autophagy, which may have significant implications for the regulation of immune responses and bacterial persistence.

BACKGROUND: Doxorubicin- (DOX-) related cardiotoxicity is a progressive degenerative loss of cardiac muscle mass and strength. This investigation aims to compare the anticipated cardioprotective effects of crocin (Cr) and dapagliflozin (DAPA) against DOX-induced cardiotoxicity, and to assess their effects on apoptosis and the Nrf-2/HO-1/NQO1 pathway. MATERIALS AND METHODS: Forty Wistar male rats were randomly divided into four groups: The control group received distilled water (DW) by oral gavage. The DOX group was given DOX 3 times/week, i.p., 2.5 mg/kg for three weeks. The Cr + DOX-treated group was intraperitoneally injected with Cr daily, concomitantly with DOX, for 12 weeks. The DAPA + DOX-treated group received DAPA daily by oral gavage concomitantly with DOX for 12 weeks. Initial fasting blood glucose (FBG), body weight, vital signs, systolic blood pressure (SBP), and electrocardiography (ECG) were recorded and then repeated monthly throughout the study period. After 12 weeks, biochemical analyses were performed. Moreover, histopathological and immunohistochemical examinations of cardiac tissue were conducteed. RESULTS: DOX significantly affected FBG and increased oxidative stress markers and proinflammatory cytokines, with hypotension, bradycardia, ECG changes, and downregulation of antioxidant genes (Nrf-2/HO-1/NQO1) mRNA. Besides, cardiac biomarkers deteriorated. Administration of either Cr or DAPA resulted in significant improvements in all tested parameters compared with DOX. However, the DAPA + DOX group showed greater improvement, particularly in some parameters. CONCLUSION: DAPA is a promising new cardioprotective medication against DOX-related cardiotoxicity. Cardiotoxicity is better controlled with DAPA than Cr by suppressing oxidative stress, apoptosis, and upregulation of the antioxidant Nrf-2/HO-1/NQO1 genes.

CONTEXT: Chronic inflammation and oxidative stress are associated with the development of chronic diseases such as diabetes, osteoarthritis (OA), and cardiovascular conditions, while avocado (Persea americana) has anti-inflammatory and antioxidant potential, which supports its nutritional and nutraceutical prescription. OBJECTIVE: In this review we sought to investigate the effects of acute and chronic consumption of avocado and its byproducts on molecular pathways related to oxi-inflammation in adults. DATA SOURCES: In this systematic review, we searched the PubMed, Embase, and Cochrane databases from May 2024 through April 2025. DATA EXTRACTION: To identify randomized clinical trials (RCTs), we used Population, Intervention, Comparator, Outcomes, Study design (PICOS) criteria and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for result presentation. The risk of bias analysis was performed using the JBI (Joanna Briggs Institute) tool. Additionally, a nutrigenomic theoretical model was developed and validated by experts to integrate clinical findings with mechanistic evidence on transcriptional pathways related to oxi-inflammation. DATA ANALYSIS: Among 982 studies identified, 14 RCTs (n = 2438) of moderate to high quality were included in this review, with 10 studies evaluating avocado pulp, 3 evaluating avocado and soy unsaponifiable (ASU), and 1 study evaluating the effect of avocado pulp and powder skin. The byproducts included fresh pulp, pulp combined with meals, freeze-dried pulp flour, and fatty acids extracted from pulp (ASU). From the 4 postprandial studies (n = 67), with doses ranging from 68  to 489 g of avocado pulp, 3 had reduction in inflammatory markers such as tumor necrosis factor α (TNF-α), nuclear factor-κB (NF-κB), and interleukin 6 (IL-6), as well as an increased total antioxidant capacity. In the 10 chronic studies (n = 2371), with a mean duration of 18.4 ± 5.6 weeks, doses of 300 mg/d of ASU or avocado in various quantities and types, concentrations of interleukin-1 beta (IL-1β), TNF-α, and oxidized low-density lipoprotein (ox-LDL) were reduced, while antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) increased in individuals with overweight, obesity, or osteoarthritis compared to the placebo control group. Among the studies, only 1 chronic study investigated gene expression of inflammatory and oxidative stress markers, highlighting a research gap in this area. Although this review was conceptually grounded in a nutrigenomics perspective, we acknowledge the limited number of RCTs directly assessing gene expression or transcriptomic outcomes. The validated model highlighted potential modulation of nuclear factor erythroid 2-related factor 2 (Nrf2-) dependent antioxidant pathways and inhibition of toll-like receptor 4 (TLR4)/NF-κB signaling by bioactive compounds from avocado and its byproducts. CONCLUSION: Despite the limited data on gene expression, the results suggest that both acute and chronic avocado consumption may beneficially modulate oxi-inflammation, especially in pro-inflammatory conditions. The theoretical model reinforces the biological plausibility of the clinical findings and provides a mechanistic framework for understanding how avocado components may influence oxi-inflammatory responses. Further studies are necessary to evaluate these effects using a molecular approach. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No. CRD42024567854.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and behavioral impairments associated with striatal neuronal loss, for which effective symptom-attenuating therapies remain lacking. Artemisinin (ART), a natural sesquiterpene lactone with established antioxidant and anti-inflammatory actions, has recently gained attention as a potential neuroprotective agent. This study evaluated the therapeutic relevance of ART in a rat model of HD induced by 3-nitropropionic acid (3-NP). 3-NP administration caused severe behavioral deficits, including an 81.8% reduction in rearing and a 74.9% reduction in ambulation (p < 0.0001), a 63.7% decrease in novel object exploration, and a 53.5% decline in Morris water maze target quadrant time versus controls. Biochemically, 3-NP elevated HMGB1 (4.8-fold), TLR4 (6.8-fold), RIPK1 (6.4-fold), RIPK3 (5.2-fold), MLKL (5.5-fold), p38-MAPK (4.2-fold), NF-κB (2.1-fold), and TNF-α (4.5-fold), while reducing GSH (57.6%), Nrf2 (77.7%), Sig1R (86.2%), D2R (64%), XIAP (77.8%), BDNF (57.6%) and SDH (61.44%) (all p < 0.0001). Treatment with ART (100 mg/kg) markedly restored behavioral performance, increasing rearing and ambulation by 3.2- and 2.6-fold, novel object exploration by 2.4-fold, and target quadrant time by 1.7-fold compared to the 3-NP group. At the molecular level, ART reduced HMGB1 (69.2%), TLR4 (60.4%), RIPK1 (66.3%), RIPK3 (66.4%), MLKL (58%), and TNF-α (62.5%), while significantly restoring GSH (2.1-fold), Nrf2 (3.7-fold), Sig1R (5.2-fold), D2R (2.6-fold), XIAP (3.7-fold), BDNF (2.3-fold) and SDH (1.94-fold) relative to 3-NP-treated rats. Collectively, these results demonstrate that ART confers robust neuroprotection against 3-NP-induced HD-like pathology by attenuating oxidative stress, suppressing HMGB1/TLR4/NF-κB signaling, inhibiting necroptosis, and upregulating neuroprotective markers. These findings highlight ART not only as a neuroprotective agent but also as a promising symptom-attenuating therapeutic candidate for Huntington's disease and other neurodegenerative disorders driven by oxidative and inflammatory stress.

Polystyrene nanoplastics (PS-NPs) are small particles derived from plastic degradation that have been detected in several human tissues. Phthalates are ubiquitous plasticizers used to increase flexibility in polymers which act as endocrine disruptors, impacting hormonal homeostasis. Considering that both pollutants have been detected in human follicular fluid, there is increasing concern regarding their potential effects on female reproductive health. This study evaluated the isolated and combined effects of environmentally relevant doses of PS-NPs and a phthalate metabolite mixture (MM) on antral follicle growth, hormone production, and the expression of genes involved in apoptosis, oxidative stress, steroidogenesis, and hormone receptor signaling. Antral follicles from adult CD-1 mice were cultured with vehicle control (DMSO and water), metabolite mixture (0.01, 0.1, 1, and 10 μg/mL), or PSNPs (5, 25, 50, and 100 μg/mL) or MM + PS-NPs (5 µg/mL PS-NPs + 0.01 µg/mL MM; 100 μg/mL PS-NPs + 10 μg/mL MM). Follicle growth was monitored every 24 h for 96 h. PS-NPs and MM were internalized by follicles and they inhibited follicle growth alone and in co-exposure. Both pollutants altered the expression of apoptosis-related (Casp3, Casp8, Bcl2) and oxidative stress-related (Cat, Nrf2, Gpx1) genes without significantly affecting steroid hormone levels. Co-exposure also reduced Esr2 and Ar expression, demonstrating more pronounced effects under low-dose combined exposure. Altogether, these findings indicate that environmentally relevant exposure to PS-NPs and phthalate mixtures impairs antral follicle growth and disrupts molecular pathways essential for ovarian function, highlighting potential pathways and the importance of understanding combined exposures in reproductive toxicity.

Lung cancer is the most prevalent cancer and cause of death; most patients present themselves at an advanced stage and continuously acquire resistance to targeted agents, antibody-drug conjugates, chemotherapy, and immune checkpoint inhibitors. In addition to secondary mutations, epigenetically driven cellular plasticity, including DNA methylation, histone modification, chromatin remodeling, RNA (m 6A)-marks, and non-coding RNAs, facilitates resistance coordination, EMT/drug-tolerant persisters, lineage switching (e.g., NSCLC to NSCLC), bypass signaling, and immune evasion by tumor cells. These states can be therapeutically rewired by epigenetic drugs: low-dose DNMT/HDAC priming restores silenced tumor-suppressor and antigen-presentation genes and activates viral-mimicry interferon signaling to augment checkpoint blockade; EZH2 and LSD1 inhibitors target plasticity and neuroendocrine programs; BET inhibition suppresses adaptive transcription; CBP/p300 modulators suppress NRF2-dependent redox survival; Combination therapies exploiting synthetic lethality through PRMT5 inhibition, applied rationally with TKIs, ICIs, chemotherapy, and antibody-drug conjugates (ADCs), are currently under clinical investigation. Biomarker-directed patient selection (e.g., MTAP loss clustering, EZH2/LSD1 activity, methylation and chromatin signatures, and liquid biopsy dynamics of methylation or ctDNA) will be critical to enrich for patients most likely to benefit. In the future, better optimized sequencing using short priming windows, intermittent dosing, and future readouts of prospective pharmacodynamics could transform transient re-sensitization into lasting control. This study aims to critically appraise mechanistic and clinical evidence linking epigenetic plasticity to therapy resistance in advanced lung cancer and to propose biomarker-directed epigenetic combination and sequencing strategies to restore drug sensitivity.

BACKGROUND: Hepatocellular carcinoma (HCC) is resistant to therapy and carries high mortality. Ferroptosis is a promising therapeutic target in which long non-coding RNAs may be involved. This study aimed to investigate the regulatory role of the PTTG3P-miR-142-5p-IGF2BP3 axis in ferroptosis during HCC, revealing the potential mechanisms by which this axis influences HCC initiation and progression. METHODS: Bioinformatics analysis revealed the expression and prognostic significance of PTTG3P in HCC. Concurrently, overexpression and knockdown models of PTTG3P, miR-142-5p, and IGF2BP3 were established to detect intracellular levels of ferroptosis regulatory factors. Gene interactions were explored via western blot, quantitative real-time PCR, and luciferase reporter assays. Finally, in vivo experiments validated the role of the PTTG3P-miR-142-5p-IGF2BP3 axis in tumorigenesis. RESULTS: PTTG3P was upregulated in HCC and associated with poor prognosis. PTTG3P was a molecular sponge for miR-142-5p, leading to IGF2BP3 derepression and modulation of ferroptosis proteins, NRF2, SLC7A11 and GPX4. PTTG3P overexpression in HepG2 cells increased ferroptosis resistance, while PTTG3P knockdown in Huh7 cells sensitized these cells to ferroptosis. Additionally, the PTTG3P/miR-142-5p/IGF2BP3 axis influenced tumor growth in a xenograft mouse model. CONCLUSION: The PTTG3P/miR-142-5p/IGF2BP3 axis is a master regulator of ferroptosis in HCC. PTTG3P is a competing endogenous RNA (ceRNA) which sustains IGF2BP3-mediated ferroptosis resistance. Targeting the axis sensitizes HCC to ferroptosis and is potentially a novel therapeutic target to combat treatment resistance.

Chronic social isolation stress (CSIS) disrupts redox homeostasis and promotes neuroinflammation, contributing to depressive-like behavior. Carvacrol (CV), a monoterpenoid phenol with antioxidants and anti-inflammatory properties, has been studied merely in stress-induced depression. Adult male NMRI mice underwent 6 weeks of CSIS and received CV (10 or 20 mg/kg, i.p.) or a positive control during the final 2 weeks. Depressive-like behavior was evaluated using open-field, splash, and forced-swim tests. Medial prefrontal cortex (mPFC) and hippocampal dentate gyrus tissues were assayed for catalase (CAT) and glutathione-S-transferase (GST) activities, reduced glutathione (GSH), and lipid peroxidation (LPO; TBARS), together with selected proinflammatory cytokines. Hematoxylin-eosin staining assessed cytoarchitecture, and molecular docking examined putative interactions of CV with the Nrf2/Keap1 complex and NF-κB. CSIS increased behavioral despair and reduced exploration and grooming, accompanied by decreased CAT, GST, and GSH, elevated TBARS, and higher inflammatory mediators, with neuronal alterations in mPFC and dentate gyrus. CV dose-dependently improved locomotor and grooming behavior, restored antioxidant defenses, reduced TBARS, and lowered inflammatory markers while preserving neuronal structure. Docking supported plausible binding (≈ -5.8 kcal/mol for Nrf2/Keap1; ≈ -5.1 kcal/mol for NF-κB), consistent with the observed molecular changes. These findings indicate that CV produces antidepressant-like effects in CSIS by reinforcing redox balance and attenuating neuroinflammation in stress-sensitive brain regions, supporting its therapeutic potential for stress-related mood disorder.

The study aims to investigate the effect of sulfasalazine (SFZN) individually and in combination with esomeprazole (ESOm) on the buccal mucosa of albino rats. SFZN is a widely used drug for the management of various autoimmune diseases which has been reported to cause renal injury in humans and a dose of 600 mg/kg/day has been described to cause renal injury in rats. ESOm is a commonly used proton pump inhibitor. Few studies have investigated their effects on oral and paraoral tissues. Three groups were designed out of 27 male albino rats. The control group was given distilled water, the SFZN group was given SFZN (600 mg/kg/day), and the ESOm group was given SFZN (600 mg/kg/day) and ESOm (30 mg/kg body weight); the drugs were dissolved in distilled water. The experiment was conducted for 14 days. Buccal mucosae were evaluated for keratin thickness, area % of iron deposition, area% of immunoreactivity to nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione (GSH) tissue level using one-way ANOVA and post hoc tests. The level of statistical significance was set at p < 0.05. SFZN individually has significantly increased keratin thickness, disrupted Nrf2 machinery and glutathione tissue level, while SFZN in combination with ESOm showed significant increase in area% of iron deposition. DNA degradation using comet assay was evaluated using Kruskal-Wallis and Dunn's test which revealed no significant difference of tail length and tail moment in SFZN group and ESOm group but these parameters were significantly different in these two groups in relation to the control group (p < 0.05).

Influenza A virus (IAV) A/PR/8/34 is a major cause of acute lung injury (ALI), with limited anti-inflammatory and antioxidant therapies. Curculigoside (CUR), a natural polyphenol, has anti-inflammatory and antioxidant activities, but its mechanisms remain unclear. This study investigated CUR's protective role in IAV-induced ALI. In vitro, A549 and MDCK cells were infected with IAV to assess CUR's effects on cell viability, inflammation, oxidative stress (OS), and barrier proteins using CCK-8 assay, ELISA, immunofluorescence, and Western blot. An IAV-induced ALI mouse model evaluated lung pathology, cytokines, OS markers, and barrier integrity. The Nrf2 inhibitor ML385 was applied to verify mechanistic involvement. CUR inhibited IAV replication, reduced cytopathic effects, and improved cell survival. It dose-dependently decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), COX-2 and iNOS, suppressed ROS and MDA, increased SOD and GSH, and restored ZO-1 and Occludin expression. In vivo, CUR alleviated weight loss, lung injury, edema, and inflammatory infiltration, while enhancing antioxidant defenses and barrier integrity. Mechanistically, CUR downregulated Keap1, promoted Nrf2 nuclear translocation, and activated Nrf2 signaling. ML385 partly reversed these effects, confirming Nrf2 involvement. CUR protects against IAV-induced ALI by inhibiting viral replication, reducing inflammation and OS, and preserving barrier function through activation of the Keap1/Nrf2 pathway.

Polystyrene microplastics (PS-MPs) have emerged as pervasive environmental contaminants with growing concerns regarding their potential adverse effects on human health; however, their impact on skeletal muscle homeostasis remains poorly understood. In this study, we investigated the effects of PS-MPs on muscle atrophy and the underlying molecular mechanism using differentiated C2C12 myotubes. Cells were exposed to 1 μm PS-MPs for 24h, which resulted in a dose-dependent increase in intracellular reactive oxygen species levels at concentrations of 100-500μg/mL. PS-MPs significantly upregulated the gene and protein expression of muscle atrophy-related markers, including myostatin, atrogin-1, MuRF1, and increased polyubiquitinated proteins, while markedly suppressed muscle protein synthesis-related markers such as MyoD1, MyoG, and MHC, as well as overall protein synthesis, as determined by puromycin labeling. Mechanistically, PS-MPs remarkably downregulated IGF-1-PI3K-Akt-mTOR signaling pathway, while concomitantly activating AMPK and FoxO3α signaling. Intracellular accumulation of PS-MPs was accompanied by mitochondrial swelling and cristae disruption. Consistently, PS-MPs induced mitochondrial dysfunction, as evidenced by mitochondrial depolarization, decreased ATP production, and reduced expression of PGC-1α, NRF1, TFAM, and OXPHOS proteins. Oxidative stress responses were further characterized by the upregulation of Keap1 and the suppression of NRF2 and HO-1 expression. PS-MPs alone elicited a muscle atrophy phenotype comparable to that caused by dexamethasone, and co-exposure synergistically enhanced the expression of atrogin-1, MuRF1, and myostatin genes. In conclusion, these findings demonstrate that PS-MPs disrupt muscle homeostasis by inhibiting IGF-1-PI3K-Akt signaling, promoting oxidative stress, and impairing mitochondrial integrity, confirming PS-MPs as a previously unrecognized environmental hazard that may contribute to muscle atrophy.

Lung cancer cells rely on protein homeostasis regulators, particularly the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. To investigate how these genetic alterations drive tumor formation, we conducted CRISPR screens on metabolically stressed murine lung cancer models and identified specific cancer dependencies, including ubiquitin ligase subunit KEAP1. Although KEAP1 is frequently mutated in aggressive non-small cell lung cancers (NSCLC, ~15%), our findings reveal an unexpected proto-oncogenic role for KEAP1 in a genetically defined subset of NSCLC. Mechanistically, Keap1 deletion activated Nrf2 and upregulated Aldh3a1. This led to elevated reductive stress and suppressed tumor growth. Given the poor prognosis of KEAP1-mutated patients, combinatorial CRISPR dropout screens revealed druggable E3s and DUBs as Keap1-dependent co-vulnerabilities. Notably, depleting these co-dependencies, such as the E3 ligases Herc2, Ubr4 and Huwe1 ablated the in vivo development of Keap1-inactivated tumors. We demonstrate that targeting the UPS represents an underexplored, promising therapeutic approach for patients with KEAP1-inactivated tumors, especially under metabolic stress.

Liver regeneration (LR) is crucial for liver function recovery, but there is still no effective treatment to promote LR. Chlorogenic acid (CGA) is the main active compound of Eucommia ulmoides Oliv., which is traditionally recorded to possess liver tonifying function. Our results revealed that CGA promoted LR in mice performed with 90% and 70% partial hepatectomy (PHx). CGA activated nuclear factor erythroid 2-related factor 2 (Nrf2) through interacting with kelch-like ECH-associated protein 1 (Keap1) during LR process. Nrf2 activation initiated the mRNA expression of E2 promoter binding factor 1 (E2F1) to accelerate cell cycle progression. Moreover, Nrf2 activation also initiated the mRNA expression of peroxisome proliferative-activated receptor, gamma, coactivator 1-alpha (PGC-1α) to promote ATP production, which supplied the sufficient energy to support LR. The importance of Nrf2 was further validated in Nrf2 knockout and liver specific Keap1 genetic depletion mice. Moreover, Arg415 residue in the kelch domain of Keap1 was proved to be pivotal for the binding of CGA with Keap1. Our findings not only highlighted the critical role of Nrf2 during LR process, but also provided a solid research foundation for exploring CGA as a promising therapeutic candidate to promote LR.

BACKGROUND: Epithelial ovarian cancer (EOC) is a highly heterogeneous malignancy with significant morbidity and mortality, and cisplatin (DDP) resistance remains a major obstacle in its treatment. Previous studies suggest that Tripterygium glycosides (TG), derived from Tripterygium wilfordii, may enhance EOC chemo-sensitivity to DDP, potentially involving gut microbiota, though the underlying mechanisms remain to be fully elucidated. PURPOSE: This study sought to determine how TG enhanced chemotherapy sensitivity in EOC and to examine the involvement of gut microbiota in this process. STUDY DESIGN: Experimental research in vivo models was conducted, including fecal microbiota transplantation (FMT) from healthy controls and validation assays with Lactobacillus paracasei. METHODS: TG were administered alone or combined with FMT to evaluate their impact on DDP sensitivity in EOC. Mechanistic studies focused on the Keap1-Nrf2-GPX4 signalling pathway and ferroptosis induction. L. paracasei was co-administered with TG to assess synergistic effects, while Nrf2 pathway activation was tested to confirm its regulatory role. RESULTS: TG significantly enhanced DDP sensitivity in EOC, either alone or synergistically with FMT. Mechanistically, TG inhibited the Keap1-Nrf2-GPX4 axis, inducing tumor ferroptosis. Gut microbiota, particularly the probiotic Lactobacillus, contributed to this effect: L. paracasei combined with TG amplified DDP cytotoxicity in EOC cells. Conversely, Nrf2 pathway activation attenuated the synergistic effect. CONCLUSION: TG sensitises EOC to DDP by suppressing the Keap1-Nrf2-GPX4 pathway to trigger ferroptosis, with gut microbiota (e.g., L. paracasei) playing a synergistic role. Combining TG and probiotics may offer a promising and innovative method to improve chemotherapy efficacy in EOC, offering a foundation for future therapeutic development.

The present study investigated the hepatoprotective effects of hesperidin (HES) encapsulated in chitosan nanoparticles (HES-CNPs) against Malathion (MAL)-induced liver toxicity in rats. Ninety male Wistar rats were randomly divided into six groups: a control group, groups treated with HES (100 mg/kg BW) or HES-CNPs (100 mg/kg BW), a MAL-exposed group (27 mg/kg BW), and two combination groups receiving MAL (27 mg/kg BW) together with either HES or HES-CNPs (100 mg/kg BW) for four consecutive weeks. MAL administration induced profound biochemical and molecular alterations in rats. It significantly reduced serum total protein and its fractions, while elevating hepatic enzyme activities, bilirubin, cholesterol, and triglycerides (TGs). Oxidative stress was evident by decreased activities of antioxidant enzymes (CAT, SOD, GPx), reduced glutathione levels, and increased malondialdehyde and reactive oxygen species (ROS). At the molecular level, MAL exposure upregulated proapoptotic genes (p53, Bax, caspase-3, caspase-9) and inflammatory markers (TNF-α, NF-κB), while down-regulating the antiapoptotic gene Bcl-2 and the cytoprotective gene Nrf2. Exposure to MAL significantly increased hepatic DNA oxidative damage, as indicated by elevated 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and DNA fragmentation. Treatment with HES-CNPs provided significantly greater protection than crude HES (p < 0.05). These hepatoprotective effects were evidenced by normalization of liver function biomarkers and lipid profile, restoration of antioxidant enzyme activities and glutathione levels, reduction of lipid peroxidation, suppression of proinflammatory and proapoptotic markers, upregulation of Nrf2 and Bcl-2, attenuation of DNA oxidative damage (8-OHdG) and fragmentation, and marked improvement of hepatic histoarchitectural and ultrastructural integrity. HES demonstrated strong binding affinity toward key proteins involved in oxidative stress, apoptosis, and inflammatory pathways, as revealed by in silico studies. In conclusion, HES-CNPs demonstrated improved hepatoprotection against MAL toxicity through the activation of the Nrf2/HO-1 antioxidant pathway and the inhibition of NF-κB/p53-mediated inflammation and apoptosis.

The oxidative stress of macrophage plays pivotal roles of acute and chronic inflammation and chronic fibrotic phases, in which the metabolic mechanism needs to be further explored. In our research, multi-omics analyses of human and murine during Benign airway stenosis (BAS) biopsy identified ACOD1 as a hallmark of immunometabolic regulation during acute inflammation stage. ACOD1 knockout aggravated both acute and chronic inflammation, which increased the granulation tissue formation. The ACOD1-itaconate axis, along with its derivative, 4-octyl itaconate (4-OI), orchestrated acute and chronic inflammation, which attenuated the fibrosis of BAS. 4-OI upregulated FTH1 expression in macrophages by activating NRF2, which effectively suppressed oxidative stress and acute inflammation. Furthermore, 4-OI promoted the packaging of FTH1 into macrophage-derived exosomes, which were transferred to fibroblasts in a SCARA5-dependent manner, inducing fibroblast ferroptosis and alleviating chronic fibrosis. In sum, this study illustrates that the ACOD1-itaconate metabolic axis decreases oxidative stress and inflammation in macrophage, which attenuates fibrosis by inducing FTH1 transfer, offering a therapeutic target for fibrotic airway diseases.

Epilepsy is a common chronic neurological disorder. Approximately one-third of patients respond poorly to existing anti-seizure medications. There is an urgent need for novel therapeutic strategies targeting the fundamental disease processes. Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides. In recent years, its role in the pathological mechanisms of epilepsy has gained increasing attention. This review systematically elaborates the core molecular mechanisms of ferroptosis. These include dysregulated iron metabolism, failure of the glutathione peroxidase 4 (GPX4) antioxidant defense system, and excessive activation of lipid peroxidation. The article focuses on summarizing experimental and clinical evidence linking ferroptosis to the onset and progression of epilepsy. It reveals key alterations in ferroptosis markers in the brain tissues of epilepsy patients and model animals. Furthermore, it delves into the complex molecular regulatory networks involved. These networks encompass neuron-glia interactions (e.g., the C-X-C Motif Chemokine Ligand 10 (CXCL10)/C-X-C Motif Chemokine Receptor 3 (CXCR3) axis), MicroRNAs/non-coding RNAs, the nuclear factor erythroid 2-related factor 2 (Nrf2), mitochondrial dysfunction, and neuroinflammation. Based on this evidence, the article further evaluates the therapeutic potential of targeting ferroptosis. This covers emerging strategies such as direct inhibitors (e.g., Ferrostatin-1), natural compounds (e.g., quercetin, boswellic acid), drug repurposing (e.g., troglitazone, D-penicillamine), gene therapy and targeted delivery systems, as well as bioinformatics-guided target discovery. Finally, this review outlines future research directions and challenges. These include elucidating cell-specific mechanisms, developing non-invasive biomarkers, optimizing combination therapies, and promoting clinical translation. The aim is to provide new perspectives and a theoretical foundation for developing disease-modifying therapies for epilepsy.

Itaconate (ITA) is a metabolite produced by immune cells such as macrophages during inflammation or infection. ITA exhibits potent immunomodulatory functions, antioxidant effects and antibacterial properties. The present study aimed to provide a systematic review of the synthesis and metabolic regulatory mechanisms of ITA and its key roles in intestinal diseases. ITA affects inflammatory bowel disease (IBD), colorectal cancer (CRC), intestinal infection and other gut disorders via the regulation of signalling pathways, including the nucleotide‑binding oligomerization domain‑like receptor protein 3 inflammasome, NF‑κB and Nrf2 pathways. ITA also modulates the composition of the gut microbiota and enhances intestinal barrier function. The present study also aimed to summarize the therapeutic potential of ITA derivatives, providing a theoretical basis for the development of novel treatment strategies for intestinal disease.

BACKGROUND: Dibutyl phthalate (DBP) is a plasticizer that bioaccumulates in organisms through multiple exposure routes. Although previous studies have documented DBP's detrimental effects on the reproductive tract, liver, and neurodevelopment, the mechanisms underlying DBP-induced thyrotoxicity are inadequately understood. OBJECTIVES: To determine whether subchronic DBP exposure induces thyrotoxicity progression via thyroid follicular cell pyroptosis mediated by the NRF2/KEAP1/NF-κB pathway. METHODS: Four-week-old male C57BL/6 mice were exposed to 50 or 250 mg/kg DBP by gavage five times weekly for 8 weeks. Systemic toxicity was assessed through body weight measurements and serum oxidative stress markers. Thyroid endocrine function and follicular morphology were evaluated via histopathological analysis. The molecular pathways regarding thyrotoxicity were determined using immunofluorescence analysis. RESULTS: DBP exposure induced systemic toxicity, as evidenced by reduced body weight and elevated serum oxidative stress markers. Thyroid dysfunction was observed, including disrupted endocrine function and altered follicular morphology, accompanied by increased apoptosis, macrophage infiltration, and excessive inflammatory cytokine production. Notably, DBP promoted pyroptosis in thyroid follicular cells, as indicated by upregulated expression of NLRP3, ASC, CASPASE-1, and GSDMD. Mechanistically, DBP suppressed the NRF2/KEAP1 antioxidative pathway while activating NF-κB signalling. CONCLUSIONS: DBP induces thyrotoxicity through oxidative stress, inflammation, and pyroptosis, mediated by NRF2/KEAP1 suppression and NF-κB activation. These results provide novel insights into the mechanisms of DBP-induced thyroid damage and highlight potential health risks associated with prolonged exposure.

Given the multifactorial aetiology of Alzheimer's disease, multi-target strategies have emerged as a promising therapeutic approach. In this study, we designed and synthesised a series of ferulic acid carbamate derivatives to selectively inhibit BuChE and stimulate Nrf2 pathway. The biological evaluation revealed that compound 5c and 5e were the most potent, exhibiting over 150-fold selectivity for BuChE. Also, 5c, 5g and 5h significantly reversed both H2O2- and Aβ-induced toxicity in HT22 cells. These compounds were further shown to eliminate ROS accumulation induced by Aβ and upregulated HO-1 and GCLM by promoting the nuclei translocation of Nrf2. In Aβ transgenic C. elegans, three lead compounds alleviated Aβ-induced paralysis and cognitive deficits. In silico study revealed that compound 5c fitted well into the active sites of BuChE and Keap1 while maintaining favourable CNS drugability. This dual strategy of cholinesterase inhibition and oxidative stress mitigation is a promising approach for novel AD therapeutics.

OBJECTIVE: This study aims to evaluate the renoprotective effects of QGDD in a DKD model exhibiting metabolic memory features and to explore its potential mechanism involving the regulation of ferroptosis via the SIRT1/Nrf2 signaling pathway. METHODS: A DKD rat model was induced using streptozotocin (STZ). The rats were assigned to the Blank Control Group (C), Model Group (M), Metformin group (Met), and low-, medium-, and high-dose QGDD groups (QGDD-L/M/H). Intervention effects were assessed by monitoring body weight, fasting blood glucose, renal function markers (24-UTP, BUN, Scr, Cys-C, β2-MG), renal histopathology (HE/Masson staining), oxidative stress markers (Fe2+, MDA, GSH, SOD), cell death indicators (TUNEL, ROS), and expression of genes and proteins associated with the SIRT1/Nrf2 pathway (RT-qPCR, Western blot). RESULTS: All QGDD dose groups decreased 24-hour urinary protein excretion and serum levels of BUN, Scr, Cys-C, and β2-MG. The medium-dose QGDD group notably reduced renal Fe2+ and MDA levels, increased GSH and SOD activity, and inhibited ROS accumulation and cellular apoptosis. QGDD activated the SIRT1/Nrf2 pathway, significantly upregulating the mRNA and protein expression of Nrf2, HO-1, and GPX4, while suppressing the accumulation of AGEs and Ferritin. CONCLUSION: QGDD mitigated the persistent elevation of AGEs, a hallmark of metabolic memory in DKD by activating the SIRT1/Nrf2 signaling pathway to inhibit ferroptosis-associated lipid peroxidation and oxidative stress. Its multi-target synergistic effects provide a solid experimental foundation for the use of Chinese herbal formulations in treating DKD. The medium-dose group demonstrated optimal therapeutic efficacy, emphasizing the significance of dose optimization.

CONTEXT: Endoscopic submucosal dissection (ESD) is the standard treatment for early gastrointestinal cancers but is often complicated by delayed healing and stenosis. Current therapies like proton pump inhibitors primarily suppress acid without actively promoting mucosal regeneration. Asiaticoside (AS), a triterpenoid from Centella asiatica, shows promise in tissue repair. OBJECTIVE: This review evaluates the therapeutic potential of AS for ESD-induced wound healing, focusing on its pharmacological mechanisms and emerging delivery strategies. METHODS: A comprehensive literature search was conducted using databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI). Relevant in vitro, preclinical, and clinical studies regarding AS, wound healing, fibrosis, and drug delivery systems were selected and synthesized to analyze efficacy and safety. RESULTS: AS accelerates healing through multifaceted mechanisms: it exerts anti-inflammatory effects via NF-κB and MAPK pathways, reduces oxidative stress through Nrf2/HO-1 signaling, and inhibits fibrosis by modulating TGF-β/Smad axes. Additionally, AS promotes angiogenesis and collagen synthesis. While clinical data supports its use in skin wounds, its gastrointestinal application is hindered by poor bioavailability. Novel delivery systems, including hydrogels and microneedles, are identified as solutions for localized, sustained release. CONCLUSION: AS offers a promising therapeutic evolution, moving from reliance on passive acid suppression toward a synergistic model that integrates acid control with active mucosal regeneration for ESD management. Future research should focus on optimizing endoscope-compatible delivery platforms to facilitate clinical translation and reduce postoperative complications.

Expanding on lung cancer CRISPR work, researchers successfully disrupted NRF2 in head and neck cancer and esophageal cancer cell types using CRISPR gene editing. Targeting exon 4 yielded the strongest results, reducing NRF2 levels by 90% and significantly increasing chemotherapy sensitivity.

The trabecular meshwork (TM) plays a pivotal role in maintaining intraocular pressure (IOP) by regulating aqueous humor outflow. Nuclear factor erythroid 2-related factor 2 (NRF2) was identified as a key transcriptional controller of TM redox balance and mitochondrial function. Transcriptomic profiling of tert-butyl hydroperoxide (tBHP)-induced oxidative injury revealed NRF2 pathway involvement in TM cellular defense. NRF2 knockout (KO) mice exhibited impaired aqueous humor dynamics, elevated IOP, and TM oxidative damage. In vitro, NRF2 knockdown aggravated oxidative stress and mitochondrial dysfunction, whereas NRF2 overexpression mitigated tBHP-induced cytotoxicity. The results of the gene set enrichment analysis (GSEA) indicated enrichment of oxidative phosphorylation pathway in NRF2-deficient cells. Chromatin immunoprecipitation sequencing (ChIP-seq) confirmed NDUFS7 as a direct NRF2 target essential for mitochondrial complex I integrity. Restoration of NDUFS7 expression in NRF2-deficient TM cells or KO mice rescued mitochondrial impairment. Collectively, these findings establish the NRF2/NDUFS7 axis as a central defense mechanism protecting TM from oxidative injury and suggest potential therapeutic strategies for glaucoma-associated ocular hypertension.

The Nrf2/Keap1 signaling axis defends against oxidative damage by regulating antioxidant and cytoprotective genes. Beyond antioxidant function, Nrf2 influences neurogenesis, synaptic plasticity, mitochondrial bioenergetics, and glial-neuronal interactions. Dysregulation contributes to Alzheimer's, Parkinson's, Huntington's, ALS, and psychiatric disorders.

Researchers used CRISPR to selectively knock down a cancer-specific version of NRF2, restoring chemotherapy efficacy in mouse models of lung squamous cell carcinoma. They exploited a tumor mutation (R34G) that creates a unique PAM site. Modest but durable editing (20-40%) was sufficient to slow tumor growth and re-sensitize them to carboplatin-paclitaxel.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that acts as a key regulator in cellular defense mechanisms against oxidative stress and xenobiotics. NRF2 modulates the expression of over 200 genes involved in antioxidant response, drug metabolism, and cellular resilience. Constitutive activation of NRF2 is a common event in cancer and recent advances provide remarkable insights into the role of NRF2 in oncogenesis, immune evasion, and treatment resistance.

At physiologically-relevant concentrations, both clinically-approved KRASG12C inhibitors Sotorasib and Adagrasib also function as inducers of NRF2. The activation of NRF2 by KRAS-G12C inhibitors represents a unique example of anti-cancer drugs which positively regulate the activity of a protein normally considered to be an oncogene.

NRF2 is regulated through post-translational modifications (PTMs) and epigenetic alterations. PTMs including phosphorylation, ubiquitination, and acetylation modulate NRF2's stability, activity, and localization. Epigenetic modifications including DNA methylation, histone modifications, and non-coding RNAs regulate NRF2 expression.

Over the last 30 years, NRF2 has evolved from being recognized as a transcription factor primarily involved in redox balance and detoxification to a well-appreciated master regulator of cellular proteostasis, metabolism and iron homeostasis. NRF2 plays a pivotal role in diverse pathologies, including cancer, and metabolic, inflammatory and neurodegenerative disorders. It exhibits a Janus-faced duality, safeguarding cellular integrity in normal cells against environmental insults to prevent disease onset, whereas in certain cancers, constitutively elevated NRF2 levels provide a tumour survival advantage, promoting progression, therapy resistance and metastasis.

This study examines NRF2 activation strategies in Alzheimer's disease, discussing how reinforcing NRF2 signaling protects against oxidative stress, neuroinflammation, and mitochondrial dysfunction that characterize AD pathology.

Persistent activation of NRF2 in malignant hepatocytes suppresses ferroptosis by restricting lipid peroxidation through GPX4, SLC7A11, and ferritin. Pharmacological strategies including NRF2 inhibitors show synergy with sorafenib.

The NRF2/BACH1 signaling axis is a promising therapeutic target. BACH1 is a transcriptional repressor that antagonizes NRF2. Non-electrophilic small molecules like HPPE simultaneously activate NRF2 and inhibit BACH1.

This study reveals Keap1 regulates muscle satellite cell quiescence by promoting Nrf2 degradation. In Keap1-null MuSCs, Nrf2 reaches intermediate levels via GSK3β-dependent degradation. In female mice, estrogen-mediated GSK3β inactivation elevates Nrf2 to peak levels, causing spontaneous quiescence exit.

This study elucidates the KEAP1-NRF2 pathway as a potential therapeutic target for EGFR-mutant NSCLC. NRF2 expression was enhanced in gefitinib-resistant cells. NRF2 inhibition with brusatol enhanced osimertinib-induced cell death and potentiated tumor growth inhibition in xenograft model.

This study investigates the role of NRF2 in esophageal squamous cell carcinoma from in vivo and clinical perspectives. Analysis of 61 biopsies found elevated NRF2, GCLM, and GPX4 expression in ESCC. GCLM overexpression conferred radiotherapy resistance.

Cisplatin resistance is a major cause of poor prognosis in NSCLC. This study demonstrates that Nrf2-sensitized cisplatin-resistant cells by enhancing ferroptosis. The Nrf2-HMOX1 pathway mediates anti-ferroptosis; inhibition with ML385 restores cisplatin sensitivity.

Ferroptosis is a distinctive process of cellular demise linked to amino acid metabolism, lipid oxidation, and iron oxidation. The ferroptosis cascade genes are among the regulatory targets of NRF2. This review provides new insights from recent discoveries involving modulation of Nrf2 and ferroptosis in lung diseases.

Hepatocellular carcinoma is a leading cause of cancer-related mortality. Nrf2 has contrasting functions: beneficial in normal liver, but harmful in HCC by promoting growth and survival. Continuous Nrf2 activation promotes advancement, aggressiveness, and immune evasion.

NRF2 constitutes a central regulator of cellular defense mechanisms, including antioxidant, anti-inflammatory and mitochondrial pathways, making it highly attractive for disease modification in neurodegenerative disorders.

This study highlights WDR23 as a specific molecular mechanism influencing NRF2 proteostasis in the hippocampus. WDR23 represents a KEAP1-independent pathway for NRF2 regulation with implications for Alzheimer's disease and cognitive function.

Microscopic hemorrhage is a common aspect of cancers. Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs cluster in perinecrotic hemorrhagic tumor regions. We identified heme as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities.

This review comprehensively covers recent progress in NRF2 inhibitor development for overcoming drug resistance in cancer. Details design principles, pharmacological properties, and therapeutic potential of various candidates.