Mitogen-activated protein kinase-interacting kinases (MNK1/2) have emerged as promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). Through scaffold-conservative optimization of an imidazo[2,1-b][1,3,4]thiadiazole core, we identified HD202A as a highly potent MNK1/2 inhibitor (IC50 = 6.1/8.1 nM) with favorable kinome selectivity within the tested kinase panel, oral bioavailability (F = 42.1%), and favorable pharmacokinetic properties. In a high-fat-diet induced MASLD mice, HD202A markedly reduced body-weight gain, hepatic triglyceride accumulation, and serum lipids while improving glucose tolerance, insulin sensitivity, and inflammatory profiles. Mechanistically, HD202A suppressed MNK-eIF4E signaling, downregulated perilipin 2 and stearoyl-coenzyme A desaturase 1, upregulated adipose triglyceride lipase and peroxisome proliferator-activated receptor gamma coactivator 1α, and enhanced mitochondrial fatty-acid oxidation and redox homeostasis. These findings validate MNK inhibition as a viable strategy for MASLD and establish HD202A as a promising lead compound for further development.

Emerging evidence implicates organelle dysfunction, particularly within peroxisomes, as a critical driver of hair follicle degeneration and alopecia. While mitochondrial defects are well characterized in the context of hair loss, the contribution of peroxisomal failure to follicular homeostasis remains largely unexplored. Here, we identify peroxisomal dysfunction as a central molecular and metabolic defect underlying hair follicle aging and loss. Comprehensive transcriptomic analysis of human dermal papilla cells from alopecia patients revealed marked downregulation of peroxisome-associated pathways, including fatty acid β-oxidation, lipid degradation, and detoxification of reactive oxygen species. These alterations were recapitulated in Nudt7-deficient mice, in which targeted disruption of peroxisomal lipid metabolism leads to pronounced hair thinning, follicle miniaturization, and exacerbated oxidative stress. To therapeutically address peroxisomal impairment, we developed catalytic nanozymes (HA-Hem) that mimic peroxisomal catalase activity. Nanozyme treatment restored metabolic balance, reduced oxidative damage, and stimulated hair follicle regeneration in both wild-type and immunodeficient murine models. Mechanistically, nanozymes increased PPARα expression, thereby enhancing peroxisomal biogenesis and lipid metabolism. Elevated PPARα further improved peroxisome and mitochondrial function and strengthened peroxisome-mitochondria interactions, resulting in coordinated restoration of cellular redox and metabolic homeostasis. Compared with minoxidil treatment, nanozyme therapy produced greater regenerative responses and maintained therapeutic efficacy in immunodeficient settings. Spatial transcriptomic analysis further demonstrated an increased expression of keratin-associated proteins and cytoskeletal genes, consistent with activation of regenerative programs. These findings support a metabolism-focused therapeutic strategy targeting peroxisomal function in the treatment of alopecia.

Rosmarinic acid (RA) is a natural polyphenol with established pleiotropic protective effects. Ifosfamide (IFA) is a potent antineoplastic agent whose clinical utility is severely limited by dose-dependent nephrotoxicity, primarily mediated by its metabolite, chloroacetaldehyde (CAA). This study aimed to investigate whether RA protects against IFA-induced nephrotoxicity and to elucidate the underlying molecular mechanisms. Male Wistar albino rats (n = 7 per group) were allocated into four groups: Control, RA-only (50mg/kg, p.o., 2 days), IFA-only (a single 500mg/kg, i.p. dose), and IFA + RA. Serum biochemical markers (urea, creatinine), renal oxidative stress parameters (MDA, GSH, SOD, CAT, GPx), gene expression levels (NF-κB, TNF-α, IL-1β, IL-17A, ACT1, TRAF6, Caspase-3, Bax, Bcl-2, PTGS2, GPX4, TfR1), and histopathological/immunohistochemical analyses (KIM-1, Nephrin, Caspase-3) were performed 24h post-administration. IFA induced severe renal dysfunction, marked oxidative stress, and extensive histopathological damage. Mechanistically, IFA initiated a pathogenic cascade activating intrinsic apoptosis and ferroptosis, driven by a self-sustaining IL-17A-TRAF6-NF-κB inflammatory loop. RA co-treatment (50mg/kg) significantly reversed all functional, biochemical, and histological damage by strategically breaking this crosstalk, restoring redox homeostasis, and simultaneously restraining both cell death programs. In conclusion, RA protects against IFA nephrotoxicity by targeting the critical inflammation-ferroptosis coupling, positioning it as a highly promising adjuvant candidate for clinical use to mitigate IFA-induced renal injury.

Abiotic stresses disrupt redox homeostasis and reduce crop productivity. Antioxidant networks support resilience by limiting excess reactive oxygen species (ROS) and maintaining redox signalling for stress perception, gene expression, and metabolic reprogramming. We summarize advances (2000–2025) in ROS generation, detoxification mechanisms, and signalling across organelles, including chloroplasts, mitochondria, peroxisomes, and the apoplast. This includes compartmentalized enzymes—superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione peroxidase (GPX), and glutathione reductase (GR)—as well as the peroxiredoxin–thioredoxin system and non-enzymatic buffers like ascorbate, glutathione, tocopherols, carotenoids, and flavonoids. We uniquely synthesize these findings in a compartment-resolved “redox rheostat” model, linking ROS concentration–time windows (signaling vs. damage) to antioxidant network design (kinetic tiers, compartmentation, and trade-offs) and identifying intervention points for breeding, genome editing, and field-scale priming. We emphasize constraints, such as NADPH supply and antioxidant recycling capacity, that lead to context-dependent outcomes. We evaluate omics, transgenic strategies, genome editing (CRISPR and Cas systems), exogenous applications, and plant–microbe associations. This synthesis clarifies how antioxidant systems protect photosynthetic and respiratory machinery while supporting signalling, thus outlining routes to climate-resilient, yield-stable crops across varied environments and stresses.

Proteostasis is the finely tuned balance of protein synthesis, folding and degradation essential for cellular health. When this equilibrium is disrupted, misfolded proteins accumulate, triggering adaptive stress responses such as the unfolded protein response and the integrated stress response (ISR). Central to the ISR is the kinase GCN2, a sensor of amino acid deprivation and ribosomal stress. Upon activation, GCN2 phosphorylates eIF2α, dampening global translation while selectively enhancing the synthesis of the stress-responsive transcription factors ATF4 and CHOP. ATF4 orchestrates a broad transcriptional programme that supports amino acid metabolism, redox homeostasis, autophagy and proteasomal degradation, which are key processes for restoring proteostasis. Beyond its canonical role, GCN2 interfaces with other regulatory networks modulating mTORC1 to promote autophagic clearance of damaged proteins and organelles, facilitating stress granule formation, and integrating signals from oxidative and endoplasmic reticulum stress to rebalance the proteome. Dysregulated GCN2 activity has been implicated in diverse pathologies including neurodegeneration, cancer and pulmonary vascular disease, positioning it as a promising therapeutic target. In this review, we explore how GCN2 links nutrient sensing to translational control and metabolic adaptation, and how its central role in proteostasis may inform new strategies for treating diseases driven by protein misfolding and stress pathway imbalance.

GABA acts as a central integrator of molecular, physiological, and metabolic responses, enhancing drought tolerance by improving water-use efficiency, osmotic balance, redox homeostasis, and stress signaling. Drought is one of the most severe abiotic stresses, limiting plant growth, yield, and global food security under climate change and resource scarcity. Gamma-aminobutyric acid (GABA), a non-proteinogenic amino acid, acts as a multifunctional regulator of plant drought tolerance by orchestrating physiological, biochemical, and molecular responses. GABA enhances osmotic adjustment, antioxidant defense, and stomatal regulation, promotes proline accumulation, and interacts with polyamines and hormonal pathways such as ABA, collectively improving water-use efficiency and mitigating oxidative stress. Its metabolism and signaling integrate diverse cellular processes, enabling efficient stress perception, adaptation, and maintenance of cellular homeostasis. GABA also coordinates metabolic crosstalk, supporting stress-responsive networks that enhance resilience under water-limited conditions. By modulating these interconnected pathways, GABA contributes to improved plant survival, growth, and productivity during drought. Exploiting GABA-mediated mechanisms offers promising strategies for enhancing crop drought tolerance, sustaining agricultural productivity, and guiding future research toward practical applications. This review synthesizes current knowledge on GABA's multifunctional role in drought adaptation, encompassing metabolic regulation, physiological responses, stomatal control, antioxidant systems, and interactions with polyamines, providing an integrated perspective on its potential to improve plant resilience under increasingly frequent and severe water-deficit conditions.

Conventional chemotherapy is significantly hampered by the inherent hydrophobicity of chemotherapeutic agents, limited tumor-specific targeting, and inadequate intratumoral accumulation, all of which undermine its clinical efficacy. Nonselective distribution of cytotoxic agents leads to suboptimal drug concentrations within tumor tissues, causing systemic toxicity in healthy organs. Tumor microenvironment-responsive nanoplatforms offer a promising strategy for enhancing specificity and efficacy. This study demonstrates the successful development of a nanodrug delivery system, CASS@PTX nanoparticles, where CASS is a cinnamaldehyde-based, disulfide-containing polymer engineered with dual-stimulus responsiveness to glutathione (GSH) depletion and reactive oxygen species (ROS) amplification. This system disrupts intracellular redox homeostasis in tumor cells, triggering the release of encapsulated paclitaxel (PTX) while enhancing chemotherapeutic efficacy through redox-dependent sensitization. GSH consumption and ROS overproduction create a prooxidative microenvironment that enhances PTX-induced apoptosis. Preclinical validation using in vitro cytotoxicity assays and in vivo tumor models demonstrates potent synergistic anti-tumor effects with minimal systemic toxicity. This cascading ROS self-generation strategy represents a promising approach for overcoming multidrug resistance and improving the therapeutic outcomes of cancer chemotherapy.

Oxidative stress and metabolic dysregulation in goblet cells are pivotal in ulcerative colitis (UC) pathogenesis. TIGAR promotes the synthesis of NADPH and contributes to mitigate oxidative stress, but how it regulates NADPH production and affects UC remains unclear. Here we demonstrate that TIGAR inhibits lactylation of the key NADPH-synthesizing enzymes G6PD (at K432) and 6PGD (at K38), thereby preserving their enzymatic activities by promoting G6PD homodimer formation and 6PGD binding to NADP+. In male UC mice, persistently low TIGAR expression elevates lactate levels, promoting the lactylation of G6PD and 6PGD and impairing their function. This process suppresses NADPH synthesis, exacerbating goblet cell oxidative stress. The resulting decline in Trx1 reductase activity induces S-nitrosylation of the mucin-processing enzyme AGR2, thereby inhibiting mature MUC2 production and compromising the intestinal mucus barrier. Our findings elucidate a mechanistic pathway through which TIGAR maintains cellular redox homeostasis, presenting it as a potential therapeutic target for UC.

Oxidative stress has emerged as a key factor regulating female fertility, reproductive aging, and the development of various gynecologic and pregnancy-associated diseases. While physiological concentrations of reactive oxygen species play a fundamental role in many aspects of normal reproduction such as folliculogenesis, oocyte maturation, implantation, and placental development, abnormal or chronic oxidative stress impairs redox homeostasis and promotes mitochondrial dysfunction, inflammation, DNA damage, and cellular senescence. Recent research interest has shifted toward next-generation dietary antioxidants, including bioactive polyphenols, carotenoids, micronutrients, and nutraceutical combinations with improved bioavailability and molecular targets. These compounds go beyond classical free-radical scavenging activity and modulate a network of redox-sensitive signaling pathways involved in autophagy, apoptosis, endocrine regulation, and immunological balance. In this review, we integrate current mechanistic advances into a cohesive framework that illustrates the regulation of key cellular processes affecting female reproductive physiology by next-generation dietary antioxidants. We also critically evaluate experimental, translational, and clinical data supporting their role in promoting reproductive outcomes, including oocyte quality, ovarian reserve, pregnancy success, and mitigation of age-related reproductive decline. We highlight their potential in the therapeutic intervention of oxidative stress-related conditions such as infertility, polycystic ovary syndrome, endometriosis, early ovarian insufficiency, and menopause-associated disorders. Finally, we discuss the current challenges associated with dosage optimization, bioavailability, long-term safety, and interindividual variability. We conclude by highlighting next-generation dietary antioxidants as a promising, widely available, and non-invasive approach to improve women’s reproductive health and promote fertility throughout their lifespan.

Vitiligo pathogenesis involves progressive melanocyte loss and keratinocyte dysfunction, which are driven primarily by oxidative stress resulting from excessive ROS accumulation. We engineered a temporally controlled hydrogel microneedle system that integrates ginseng-derived exosomes (G-Exos) with biomimetic polydopamine nanoparticles (PDA@PEGs) to concurrently target the pathogenic triad of vitiligo, including oxidative stress, inflammation, and melanocyte deficiency. This system employs methacrylated hyaluronic acid (HAMA) hydrogel microneedles for rapid PDA@PEG release while utilizing glyceryl monostearate micelles to achieve matrix metalloproteinase-9 (MMP-9)-responsive G-Exo release at inflammatory foci, enabling intelligent spatiotemporal control. Functionally, G-Exos help restore redox homeostasis and suppress inflammation through bioactive constituents, thereby protecting melanocytes and enhancing keratinocyte proliferation. Moreover, PDA@PEG promotes repigmentation through the dual mechanisms of exogenous melanin deposition and endogenous melanogenesis stimulation. In murine models, this strategy achieves significant repigmentation within 3 weeks by activating follicular stem cells, upregulating melanogenic markers (Tyr/Mc1r), increasing antioxidant defense (ApoE), and suppressing inflammatory signaling (IL-17). This natural-biomimetic hybrid design leverages biocompatible materials to co-target multiple pathological axes, offering a novel self-adaptive approach for microenvironmental rehabilitation in vitiligo.

Oocyte vitrification imposes oxidative stress that compromises maturation competence. Aquaporin-7 (AQP7) has been implicated in cellular redox regulation, but its specific role in cryopreserved oocytes remains unclear. Here, germinal vesicle (GV) stage oocytes were vitrified and warmed with AQP7 inhibitor Z433927330 (0.5, 5, 50 μM). AQP7 inhibition disrupted redox balance, compromised mitochondrial function. Consequently, it severely compromised developmental competence, leading to significantly reduced cleavage (39.90% ± 6.17 vs. 52.93% ± 3.37) and blastocyst formation rates (1.67% ± 2.89 vs. 5.17% ± 2.49) in vitro. To confirm, we performed microinjection-mediated AQP7 knockdown and overexpression and assessed their effects on maturation. AQP7 knockdown further reduced the maturation rate of vitrified oocytes (20.22% ± 3.14 vs. 36.31% ± 2.10), whereas overexpression partially restored it (43.98% ± 4.71 vs. 33.74% ± 2.21). The mitochondrial-targeted antioxidant MitoQ partially rescued the maturation rate (53.13% ± 2.75 vs. 43.52% ± 2.71). Thus, AQP7 is essential for the maturation of vitrified sheep oocytes by safeguarding intracellular redox homeostasis, thereby preventing mitochondrial dysfunction and cytoskeletal damage, and loss of embryonic developmental potential.

PROMETHAZINE PROVOKES BEHAVIORAL ALTERATIONS AND DISRUPTS REDOX HOMEOSTASIS IN PLANARIANS.

Recent advances in ROS-modulating materials for sepsis treatment.

Lens aging and disease: Molecular mechanisms, functional consequences, and pharmacological implications.

EROS protein: Decoding its pivotal role in redox homeostasis and disease pathogenesis

SLC25A39 binds and modulates PRDX1 to suppress ROS-induced necroptosis in hepatocellular carcinoma.

Biosensors reveal subcellular redox status in live cells.

Plasma protein signatures associated with functional outcome heterogeneity in rtPA-treated acute ischemic stroke.

The MafG/Bach1-Lcn2 transcriptional axis drives ferroptosis in sepsis-induced acute lung injury via disrupting redox homeostasis.

Targeting PPP1R15B and ATF4 axis in hepatocellular carcinoma: A novel strategy for overcoming lenvatinib-tolerant persister cells through GPX4-mediated ferroptosis induction.