Search Results (686)

Heme is a crucial cofactor involved in various biological processes, such as electron transport, catalysis, and oxygen binding. Understanding the binding of heme to heme-binding proteins (HBPs) is essential for clarifying their functions and molecular mechanisms and for applications in enzyme engineering and therapeutic development. AlphaFold3 (AF3), an artificial intelligence (AI)-based macromolecular prediction tool, has been applied to the structural modeling of various proteins, including HBPs. Nevertheless, whether AF3 provides reliable structural information for HBPs has not yet been investigated. To determine the AF3 predictions for HBPs, the apo and holo states of four human HBPs, including the cytochrome b5 domain of sulfite oxidase (SO-b5), the cytochrome b5 domain of NADH cytochrome b5 oxidoreductase (Ncb5or-b5), cytochrome b5 type B (CYB5B), and neuroglobin (NGB), generated by AF3, were examined and compared with experimental HBP structures. The overall positions of the heme molecules were well docked into the heme-binding pockets of HBPs; however, there were differences in the heme-binding configurations, including pocket geometry and coordination environment, which are crucial for functional interpretation. The experimental NGB structure contains a disulfide bond near the heme-binding region, whereas the AF3-predicted model lacks this bond, causing differences in local folding that affect the heme-binding environment. Molecular dynamics simulations demonstrated that the AF3-predicted NGB structure exhibited distinct molecular conformations and flexibility compared with the experimental structure. These data indicate both the potential and the limitations of using AF3-predicted structures to model the heme-binding states of HBPs. Full article

Asthma is a heterogeneous chronic airway disease in which oxidative stress (OS) plays a central mechanistic role beyond classical immune-mediated inflammation. Reactive oxygen and nitrogen species (ROS/RNS), generated by recruited inflammatory cells and activated airway structural cells, drive epithelial injury, mucus hypersecretion, airway remodeling, and modulate key transcription factors including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. This review synthesizes current evidence on the multilevel redox-based determinants of asthma severity, spanning from genetic polymorphisms to circulating biomarkers. We examine serum antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxiredoxins (PRDXs), and the thioredoxin (Trx) system as dynamic indicators of systemic redox status and disease severity, alongside oxidative enzymes including NADPH oxidases and dual oxidases (NOX/DUOX), xanthine oxidase (XO), and myeloperoxidase (MPO) that serve as upstream sources of airway oxidant burden. Functional genetic polymorphisms in antioxidant genes (SOD2, CAT, glutathione S-transferase mu 1/glutathione S-transferase theta 1 (GSTM1/GSTT1), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/KEAP1)) and oxidative enzyme genes including nitric oxide synthase 1/2/3 (NOS1/2/3), MPO, cytochrome b-245 alpha chain (CYBA), and xanthine dehydrogenase (XDH) are reviewed as modulators of individual redox capacity and asthma susceptibility, with particular attention to gene–environment interactions. We further discuss oxidative damage biomarkers, including malondialdehyde (MDA), 8-isoprostanes, 4-hydroxynonenal, 8-oxo-7, 8-dihydro-2′-deoxyguanosine, protein carbonyls, 3-nitrotyrosine, and advanced oxidation protein products as indicators of lipid, DNA, and protein oxidation that correlate with disease activity and control. The roles of micronutrient cofactors in modulating antioxidant enzyme function and their potential as contextual biomarkers are also addressed. Additionally, emerging evidence on microRNAs (miRNAs) linked to OS biology in asthma is presented. Finally, we critically evaluate the challenges limiting clinical translation, including biomarker non-specificity, analytical variability, gene–environment complexity, and the absence of standardized reference ranges. This integrated framework supports the development of multilevel redox prognostic panels combining genetic, enzymatic, and oxidative damage readouts for improved asthma phenotyping, severity stratification, and personalized therapeutic approaches. Full article

Iron deficiency is a major global health concern, primarily attributable to inadequate dietary intake and limited absorption of iron. Foliar fertilization of vegetables like bell pepper (Capsicum annuum) may increase their iron content. When especially rich in ascorbic acid, intestinal iron absorption might be improved even further. However, iron content in foods and/or bioaccessibility after in vitro digestion alone would be unreliable predictors of iron bioavailability. Consequently, it seems to be necessary to reconsider digestion models and bioavailability evaluation. The objective of this study was to establish a mucin-enhanced in vitro digestion model to assess the bioavailability of non-heme iron from food matrices in combination with the widely utilized Caco-2 model of intestinal iron absorption. Compared with Fe(III), incubation with 20 µM and 200 µM Fe(II) sulfate increased ferritin formation (normalized to total protein (TP)) in differentiated Caco-2 cells by 80% and 130%, respectively. Furthermore, no loss of cellular viability was observed across the tested Fe(II) and Fe(III) concentrations (20–2000 µM). Three in vitro digestion models (DIN, DIN-lite, and DIN+G), differing mainly in digestive enzyme content, were evaluated for iron bioaccessibility and bioavailability. Only DIN-lite and DIN+G were compatible with Caco-2 cells. Although DIN-lite yielded 25% higher bioaccessible iron than DIN+G, both models resulted in comparable ferritin formation in Caco-2 cells. The DIN+G/Caco-2 model was applied to bell pepper cultivars (‘Ferrari’, ‘Morbidelli’, and ‘Jack Miller’), treated with foliar Fe(II) sprays during cultivation, achieving up to 3.9-fold increased iron content. However, this increase did not translate into enhanced in vitro iron bioavailability in the bell pepper pericarp. Consistent with previous studies, these findings indicate that iron content and bioaccessibility alone are insufficient predictors of iron bioavailability in plant-based foods. At the same time, the mucin-enhanced DIN+G/Caco-2 model proved to be a suitable approach for investigating iron bioavailability in plants. Full article

Photobiomodulation (PBM) is a non-invasive therapeutic strategy that uses red and near-infrared (NIR) light in the 590–950 nm range to modulate the cellular and molecular pathways involved in retinal homeostasis. At the molecular level, PBM acts primarily through photon absorption by cytochrome c oxidase (CcO, complex IV of the mitochondrial electron transport chain), whose four metal centres—two copper (CuA and CuB) and two heme groups (heme a and heme a₃)—absorb light across approximately 600–1000 nm. Photon capture promotes photodissociation of inhibitory nitric oxide (NO) from the binuclear CuB–heme a₃ centre, accelerates electron transfer, restores the proton-motive force and increases ATP synthesis. These primary events trigger a coordinated molecular programme that includes (i) transient mitochondrial reactive oxygen species (ROS) bursts that activate the Nrf2/Keap1/ARE axis and upregulate phase II antioxidant enzymes (HO-1, NQO1, GCLC, SOD2, catalase, GPx); (ii) calcium- and cAMP-dependent secondary signalling that converges on PI3K/Akt, MAPK/ERK, AMPK and mTOR pathways; (iii) suppression of NF-κB-driven cytokine production (TNF-α, IL-1β, IL-6) and of NLRP3 inflammasome activation; (iv) downregulation of the HIF-1α/VEGF axis, particularly at 590 nm; (v) anti-apoptotic remodelling of the Bcl-2/Bax ratio with reduced cytochrome c release and caspase-3/9 activation; and (vi) PGC-1α/TFAM/NRF1-driven mitochondrial biogenesis, alongside restoration of fission/fusion homeostasis (Drp1, Mfn1/2, Opa1) and PINK1/Parkin-mediated mitophagy. Wavelength specificity has a defined molecular basis: 590 nm modulates VEGF signalling and RPE pump activity, 660 nm interacts with the CuB centre and enhances O₂ binding at CcO, and 850 nm is absorbed by CuA and supports electron entry into complex IV. A second molecular axis is the bidirectional crosstalk between PBM and the circadian system: mitochondrial respiration, ATP turnover and CcO activity oscillate over the 24 h cycle under the control of the BMAL1/CLOCK and PER/CRY core machinery, the NAD⁺/SIRT1–SIRT3 axis and REV-ERBα. Preliminary preclinical and human observations suggest that NIR-induced bioenergetic and functional gains may be coupled to this rhythm, with greater benefit reported when light is delivered in the morning window (≈08:00–11:00); this time dependence should be regarded as an emerging hypothesis rather than an established clinical principle. The clinical evidence is unevenly developed across indications. It is most robust for non-exudative age-related macular degeneration, where multiwavelength PBM (590/660/850 nm; Valeda Light Delivery System) has shown disease-modifying potential in randomized controlled trials (LIGHTSITE I–III and the LIGHTSITE IIIB extension), with sustained BCVA gains and reduced incidence of geographic atrophy over 24 months and beyond. Evidence for retinitis pigmentosa, central serous chorioretinopathy and, with red-light monotherapy, childhood myopia is at present limited to small or short-term studies and remains preliminary. This narrative review synthesizes the molecular machinery engaged by PBM, integrates clinical findings across retinal diseases and discusses how chronotherapeutic delivery of light, aligned with the molecular clock, may further optimize therapeutic efficacy. Full article

Bonellia viridis, an echiuran polychaete that inhabits infralittoral rocky habitats around the Atlantic, Mediterranean, and Southeastern Pacific coastlines, exhibits environmentally mediated sexual dimorphism: planktonic larvae develop into dwarf males after exposure to bonellin, a green pigment produced by adult females. Bonellin is a chlorin with a structure consistent with derivation from uroporphyrinogen III, the last universal precursor of all known tetrapyrroles, yet its biosynthesis remains unknown. Here, the de novo genome assembly for a single adult female specimen of B. viridis isolated from Okinawa has been generated (via Illumina sequencing) and found to comprise 429.95 Mb across 95,859 contigs, with an N50 of 6505 bp, recovering 83.3% of near-universal metazoan BUSCO orthologs. Homologs of all canonical enzymes of the heme biosynthetic pathway (termed hem genes) were identified across the genome. The genomic resources establish a foundation for research into the biochemical basis of pigment production, chemically mediated sex determination, and the distinct biology of B. viridis. Full article

Castration-resistant prostate cancer (CRPC) remains a significant clinical challenge due to the ability of tumor cells to undergo intratumoral androgen synthesis, a process catalyzed by the CYP17A1 enzyme. The only CYP17A1 inhibitor available in therapy, abiraterone acetate, faces significant limitations due to its steroidal structure, which causes off-target effects and generates agonistic metabolites that paradoxically stimulate the androgen receptor (AR). This study presents the development of the D2AAK1M series, a novel class of non-steroidal potential CYP17A1 inhibitors based on a pyridine–piperidine scaffold. Through biomimetic design and molecular docking, we demonstrated that these compounds have the potential to coordinate the heme iron while achieving high shape complementarity within the catalytic pocket. In silico ADME profiling indicated superior physicochemical properties compared to abiraterone, including optimal lipophilicity, enhanced water solubility, and the potential to penetrate the blood–brain barrier for targeting CNS metastases. In vitro assay results correlated with a suggested mechanism, showing preferential cytotoxicity toward androgen-dependent LNCaP cells (AR+) while sparing AR-negative lines (DU145, PC3) and healthy human fibroblasts (BJ). Our compounds present a promising starting point for further development of non-steroidal CYP17A1 inhibitors. Full article

Ultraviolet A (UVA) radiation disrupts the redox balance of melanocytes and may lead to the development of melanoma, highlighting the need for new skin protection strategies. This study assessed the effect of phytocannabinoids [cannabigerol (CBG), cannabidiol (CBD), and CBG + CBD] on redox homeostasis in control and UVA-exposed melanocytes and in melanoma cells (SK-Mel-5). UVA radiation increased the activity of prooxidant enzymes in both melanocytes and SK-Mel-5 cells and, consequently, the level of reactive oxygen species (ROS) (approx. 2-fold). It also activated nuclear factor erythroid 2 (Nrf2), as reflected by increased expression of heme oxygenase 1 (HO-1) (melanocytes approx. 2-fold; SK-Mel-5 approx. 7-fold). Concomitantly, antioxidant mechanisms were impaired, as demonstrated by reduced superoxide dismutase (SOD1/SOD2) activity and impaired glutathione and thioredoxin function. These changes were accompanied by increased levels of oxidative damage markers (isoprostanes, 4-hydroxynonenal-4-HNE, and 4-HNE-protein adducts) (43–100%) and increased inflammatory signaling, including increased expression of nuclear factor kappa B (NF-κB) subunits (melanocytes: p52 ~2-fold, p65 ~75%; SK-Mel-5: ~4–4.5-fold) and tumor necrosis factor alpha (TNF-α; ~30%). Phytocannabinoid treatment modulated these UVA-induced changes. In SK-Mel-5 cells, phytocannabinoids normalized the activity of prooxidant enzymes and consequently reduced ROS levels (~30%). They also reduced Nrf2 activation and HO-1 expression; however, CBG increased HO-1 level in melanocytes (~25–40%). Furthermore, phytocannabinoids enhanced antioxidant defense by increasing SOD activity, particularly in melanocytes (~10–40%), and restoring the glutathione and thioredoxin systems. Markers of oxidative damage were reduced by approximately 23–37% after treatment. Furthermore, phytocannabinoids attenuated NF-κB activation (p52 ~18–28%, p65 ~25–29% in melanocytes; ~20% in SK-Mel-5), while TNF-α levels remained unchanged. The effects in non-irradiated cells were modest (<15%). These results suggest that phytocannabinoid-mediated modulation of redox balance may stabilize melanocytes exposed to UVA radiation and potentially reduce the risk of neoplastic transformation. However, the observed protective effects in SK-Mel-5 cells require further investigation and detailed molecular analysis. Full article

Chlorine dioxide (ClO₂) is a neutral oxidant molecule with a short lifespan once in contact with electron donors (organic matter). ClO₂ solutions have antiviral, antibacterial, antifungal, anti-protozoan, anti-inflammatory, anticancer, and wound-healing activity and it was used at safe concentrations on patients from different countries during the COVID-19 pandemic. In Mexico, 1067 COVID-19 patients received compassionate treatments with ClO₂ during the 2020/2021 pandemic years. We describe the treatments and clinical reports of these patients, as it concerns the oxygen saturation (SpO₂) recovery, and provide a biochemical explanation. The number of healed patients was 1057, >99% of the total and SpO₂ showed a hyperbolic fast increase. This might happen because ClO₂ attracts one electron from the organic matter and produces a chlorite anion (${\mathrm{ClO}}_2^{-}$). This new molecule is known to exhibit metabolic activity in the blood stream. On the one hand, it will perform the aforementioned antibiotic and healing properties. On the other hand, it will also allow the production of oxygen (O₂) to be transported by the Oxyhemoglobin. This reaction is mediated by an intermediate state of a ferryl molecule (Fe=O) in the allosteric heme site of methemoglobin, which behaves as a reductase enzyme. This reaction can explain the rapid and steady increase in O₂ saturation in healed patients. Full article

The flower color of Rhododendron is primarily determined by anthocyanin biosynthesis, with cytochrome P450 CYP75 family members, particularly flavonoid 3′,5′-hydroxylase (F3′5′H), playing a central role. However, the composition and functional characterization of CYP75 genes in Rhododendron remain insufficiently explored. This study performed genome-wide identification of the CYP75 gene family using the Rhododendron simsii reference genome and functionally characterized the corresponding F3′5′H homolog cloned from Rhododendron × hybridum petals (red cultivar and pink cultivar). Seven RsCYP75 genes were identified, categorized into two subfamilies: RsCYP75A (A1–A5) and RsCYP75B (B1–B2), with a prominent cluster on chromosome 13. All encoded proteins contained a conserved cytochrome P450 domain and typical heme-binding motifs. Among these, RhCYP75A2 showed the highest expression level in red petals at full blooming period and was designated as RhF3′5′H. RhF3′5′H encodes a basic membrane protein with the characteristic F3′5′H motif, with its transcript most abundant in flowers. Transient overexpression of RhF3′5′H in red R. × hybridum petals resulted in a 9.74-fold increase in its transcript levels and a 1.25-fold increase in anthocyanin content compared to that in the control accompanied by the up-regulation of CHS, F3H, DFR and ANS. Conversely, RhF3′5′H silencing reduced anthocyanin accumulation but increased CHS and F3H transcript levels, suggesting a compensatory transcriptional response in the upstream anthocyanin pathway. Moreover, RhF3′5′H was heterologously expressed in E. coli Rosetta as an MBP fusion protein, purified, and identified by LC-MS/MS and ELISA. The protein showed the ability to promote anthocyanin accumulation. Molecular docking analysis demonstrated that RhF3′5′H can bind to naringenin and dihydrokaempferol. These results confirm that RhF3′5′H is a functional F3′5′H-type CYP75A enzyme and a positive regulator of anthocyanin accumulation in Rhododendron petals. This work enriches the CYP75 gene catalog in Rhododendron and provides candidate genes for future studies on flower color regulation and molecular breeding. Full article

Basal blood pressure (BP) is partly determined by systemic vascular resistance, which is modulated by vasoactive pathways, including gaseous messengers. Carbon monoxide (CO), continuously generated by the constitutive enzyme heme oxygenase-2 (HO-2) encoded by HMOX2, promotes vascular smooth muscle relaxation and may contribute to interindividual variability in resting BP. The functional single-nucleotide polymorphism rs4786504_T>C has been associated with higher HMOX2 expression in C-allele carriers, providing a plausible biological link between genetic variation in the HO-2/CO pathway and vascular redox signaling. We investigated this association in forty young, healthy, normotensive adults studied under controlled laboratory conditions during a 4-day sleep deprivation protocol, with repeated standardized daytime BP measurements (478 observations). Linear mixed-effects models were adjusted for major physiological and behavioral covariates. T-allele carriers (C/T + T/T) exhibited higher diastolic BP (β = +6.08 mmHg, 95%CI [1.32–10.84], p = 0.017) and mean arterial pressure (β = +5.28 mmHg, 95%CI [0.28–10.29], p = 0.046) than C/C homozygotes, with no effect on systolic BP or heart rate. The association remained consistent across sensitivity and additive genetic models. This hypothesis-generating study provides preliminary evidence in humans, albeit limited by sample size, of a link between a functional HMOX2 variant and resting BP, consistent with a possible contribution of constitutive HO-2 activity to BP regulation. Full article

Vaccinium bracteatum Thunb. leaves (VBTL), a traditional medicinal plant historically consumed as food in certain regions of China, have been documented to possess potent in vitro antioxidant activity. However, its in vivo anti-aging effects and underlying mechanisms remain to be fully elucidated. Therefore, this study aimed to evaluate its anti-aging efficacy to support its potential value as a functional food constituent for healthy aging. Anti-aging efficacy was systematically assessed using D-galactose-induced aging mice, a Caenorhabditis elegans model, and an H₂O₂-induced cellular senescence model. Key active constituents were identified via untargeted metabolomics. In D-galactose-induced aging mice, VBTL extracts effectively ameliorated oxidative stress, significantly increasing the activities of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), while reducing malondialdehyde (MDA) levels. In Caenorhabditis elegans, VBTL extended lifespan, reduced lipofuscin accumulation, and demonstrated no reproductive toxicity. Untargeted metabolomics identified xanthotoxol as a key active constituent, which was then selected for mechanistic investigation. In a cellular senescence model, xanthotoxol alleviated H₂O₂-induced oxidative stress, significantly enhanced SOD activity, reduced reactive oxygen species (ROS) and MDA levels, inhibited senescence-associated β-galactosidase (SA-β-gal) activity and the expression of senescence-associated secretory phenotype (SASP) factors (IL-6, MMP1, MMP3), and downregulated the expression of genes in the P53/P21/P16 signaling pathway. Mechanistically, xanthotoxol activated the Nrf2 signaling pathway, promoting the expression of its downstream targets heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). This study demonstrates that VBTL and its active compound xanthotoxol exert anti-aging effects across multiple models by modulating the Nrf2 pathway, providing both theoretical and experimental foundations for developing VBTL as a novel, safe, and effective natural ingredient in anti-aging functional foods. Full article

Liver diseases, including fatty liver, hepatitis, and cirrhosis, remain major global health challenges due to their disruption of metabolic homeostasis and detoxification processes. Redox imbalance plays a central role in liver disease progression by promoting inflammation, hepatic stellate cell activation, mitochondrial dysfunction, and fibrogenesis. Although flavonoids have historically been considered direct reactive oxygen species (ROS) scavengers, emerging evidence indicates that their biological effect at physiological concentrations are primarily mediated through modulation of intracellular redox signalling rather than simple radical neutralisation. This review highlights flavonoids as redox-modulating agents capable of restoring hepatic redox homeostasis through coordinated regulation of molecular pathways. Mechanistically, flavonoids activate the Nrf2-Keap1 axis to enhance endogenous antioxidant defences, including heme oxygenase-1 and glutathione biosynthesis enzyme, while suppressing NF-κB-mediated pro-inflammatory signalling and modulating MAPK and PI3K/Akt pathways. They also regulate mitochondrial redox balance, supporting mitophagy, metabolic adaptation, and cellular resilience to oxidative stress. In addition, flavonoid biotransformation by the gut microbiome improves intestinal barrier integrity, reduces endotoxin-driven hepatic inflammation, and contributes to gut–liver crosstalk. Collectively, these mechanisms position dietary flavonoids as multi-target redox modulators with promising therapeutic potential in chronic liver disease, although further studies are needed to improve their bioavailability and clinical translation. Full article

As the key enzyme catalyzing the final step in heme and chlorophyll biosynthesis, protoporphyrinogen oxidase (PPO) is a crucial target for herbicide development. To date, over 40 PPO inhibitors have been commercialized. They offer high efficacy, environmental safety, low application rates, and broad-spectrum weed control. Recently, significant progress has been made in PPO structural biology, with several crystal structures resolved. Despite decades of use, the emergence of resistant weeds necessitates the continuous innovation of novel PPO inhibitors. This review systematically summarizes PPO three-dimensional structures, enzyme-inhibitor interaction mechanisms, and quantitative structure–activity relationships (QSARs). Finally, we outline rational molecular design strategies for the next generation of PPO inhibitors. Full article

Background/Objectives: Many chronic diseases, including cancer, can be developed in conjunction with excessive intracellular oxidative stress and persistent inflammation. The importance of preventive strategies is highlighted by the potential of phytochemical interventions to mitigate these diseases. The purpose of this study was to investigate how Citrus depressa leaf (CDL) extracts can prevent 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced carcinogenesis in JB6 P+ mouse skin epidermal cells. Methods: CDL extracts were prepared and characterized for their phenolic and flavonoid contents. Effects of the potent extract on cell viability, TPA-induced colony formation, intracellular reactive oxygen species (ROS) levels, and nuclear factor erythroid 2–related factor 2 (Nrf2)-related protein and mRNA expression, mediated by epigenetic modifications, were evaluated in JB6 P+ cells. Results: Both the water extract (CDL-WE) and the 95% ethanol extract (CDL-95EE) contain abundant flavonoids that inhibit TPA-induced cell transformation and colony formation without minimal cytotoxicity. Mechanistic studies indicated that CDL-95EE increased the gene expression of Nrf2-related detoxification and antioxidant enzymes, such as UDP-glucuronosyltransferase 1A (UGT1A) and heme oxygenase-1 (HO-1), and decreased intracellular ROS accumulation. Furthermore, CDL-95EE reduced the expression of epigenetic modifiers, including DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), suggesting involvement in epigenetic regulation. Conclusions: These findings indicate that CDL, an agricultural by-product, may be useful in cancer prevention through antioxidant and epigenetic mechanisms. Full article

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by high metabolic activity, chronic endoplasmic reticulum stress, and persistent redox imbalance. Excessive immunoglobulin synthesis and adaptation to the hypoxic bone marrow microenvironment lead to sustained production of reactive oxygen species (ROS). Their excessive accumulation promotes genomic instability, disease progression, osteolytic bone disease, and resistance to therapy. Paradoxically, MM cells adapt to oxidative stress by activating antioxidant and metabolic defense mechanisms, including Nuclear factor erythroid 2-related factor 2 (NRF2)- and Heme Oxygenase 1 (HMOX1)-dependent pathways, metabolic reprogramming, and overexpression of ROS-scavenging enzymes such as peroxiredoxin 6 (PRDX6), allowing survival at the threshold of oxidative toxicity. Evidence indicates that biomarkers of oxidative stress—such as lipid and protein oxidation products, antioxidant enzyme activity, and the Oxidative Stress Score—correlate with disease stage, prognosis, and treatment response. Redox-modulating therapeutic strategies, including pharmacological ROS induction, inhibition of antioxidant defenses, and the use of natural pro-oxidant compounds, are emerging as promising adjuncts to standard MM therapies. Recent studies also highlight the gut microbiota as an indirect regulator of oxidative balance, immune modulation, and metabolic homeostasis in MM. This review summarizes current knowledge on oxidative stress in multiple myeloma, emphasizing its role in pathogenesis, drug resistance, biomarker development, and emerging therapeutic and supportive strategies. Full article