The story begins at the ribosome. DON binds to the peptidyl transferase center of the ribosome, stalling protein synthesis and triggering what toxicologists call the ribotoxic stress response, or RSR. The review frames this as the direct RSR—the initial spark of DON toxicity. When ribosomes sense that translation has been interrupted, they activate a family of stress kinases, most notably the mitogen-activated protein kinases p38, ERK1/2 and JNK. These kinases are normally the cell’s emergency messengers, marshaling responses to infection and injury. Under DON’s influence, however, they are pressed into a pathological program: they phosphorylate transcription factors that switch on genes for inflammatory cytokines such as interleukin-8, tumor necrosis factor-alpha and interleukin-6, and they push cells toward apoptosis when the damage proves irreparable.

What makes the new synthesis particularly valuable is its emphasis on amplification loops. The ribotoxic stress response does not act alone. The authors describe how DON exposure generates reactive oxygen species, overwhelming the cell’s antioxidant defenses, and simultaneously provokes endoplasmic reticulum stress, in which misfolded proteins accumulate and activate the unfolded protein response. These two secondary stressors feed back into the primary signaling network, creating a self-reinforcing spiral. Mitochondria become collateral damage: DON disrupts mitochondrial membrane potential and dynamics, in part through proteins such as Drp-1, releasing cytochrome c and other factors that commit the cell to programmed death. The review highlights that this mitochondrial dysfunction is not a side effect but a central node in the toxicity network, linking the initial ribosomal insult to downstream apoptosis and, increasingly recognized, ferroptosis—an iron-dependent form of cell death driven by lipid peroxidation.

The signaling crosstalk extends well beyond MAPK. The review maps how DON engages the PI3K/AKT/mTOR pathway, whose inhibition triggers autophagy and contributes to apoptosis in intestinal epithelial cells; the NF-κB pathway, a master regulator of inflammation whose chronic activation erodes the gut barrier; the JAK2/STAT3 axis, which at non-cytotoxic concentrations can paradoxically aggravate inflammatory responses; the Nrf2/Keap1 system, the cell’s principal antioxidant defense, which DON suppresses; and the Wnt/β-catenin pathway, which governs intestinal stem cell renewal and is dampened by the toxin, impairing the gut’s capacity to repair itself. Each of these pathways has been studied in isolation, but the review’s central argument is that DON’s real toxicity emerges from their synergy—a network-level derangement rather than a single broken switch.

The consequences ripple across multiple organ systems. In the intestine, the first tissue to encounter dietary DON, the toxin disrupts tight junctions through RhoA/ROCK-mediated signaling and F-actin disassembly, thins the mucus layer by suppressing trefoil factors and mucins in goblet cells, and weakens the epithelial barrier enough to permit translocation of bacteria and other luminal contents. Studies in piglets—the most relevant large-animal model for human gastrointestinal physiology—show that DON-challenged animals suffer intestinal damage and systemic inflammation driven by NF-κB activation. Worryingly, recent work cited in the review suggests that pre-exposure to DON can alter how intestinal epithelial cells respond to pathogenic E. coli infection, hinting that the toxin primes the gut for secondary disease.

The immune system is equally vulnerable, and in a dose-dependent, sometimes paradoxical way. At low concentrations, DON stimulates proinflammatory gene expression, while at higher doses it kills immune cells outright, producing immunosuppression. The review documents effects on thymic epithelial cells, T-cell lines, macrophages and lymphocytes, including oxidative DNA damage in poultry lymphocytes. DON also compromises innate immune responses to bacterial pathogens such as Listeria monocytogenes by inhibiting TLR2/NF-κB signaling in hepatocytes, and it promotes uptake of Salmonella typhimurium by macrophages through ERK1/2-driven cytoskeletal remodeling. Perhaps most unsettling is emerging evidence that DON can drive antibiotic resistance evolution in Bacillus cereus through cell wall remodeling, adding an antimicrobial-resistance dimension to a toxin already implicated in foodborne disease facilitation.

Beyond the gut and immune system, the review surveys DON’s neurotoxicity and reproductive toxicity. In the nervous system, DON induces apoptosis in hippocampal neurons via the MAPK pathway, triggers mitochondrial dysfunction in neuronal models, and in weaned piglets is associated with lipid peroxidation, dampened neurotransmitter levels and disturbed calcium signaling. Recent multi-omics work points to a microbial-gut-brain axis through which DON suppresses appetite, helping to explain the feed refusal that gives vomitoxin its name. On the reproductive front, oocytes are especially susceptible during meiotic spindle formation: DON exposure causes aneuploidy, abnormal embryo development, epigenetic modification changes and autophagy-apoptosis shifts in maturing oocytes. In males, the toxin induces testicular ferroptosis by disrupting the Nrf2/system xc-/GPX4 axis, and it has been shown to impair boar semen quality. Recent studies even implicate a glycolysis-H3K18la-STEAP3 axis in DON-driven ovarian ferroptosis in piglets.

Against this mechanistic backdrop, the review evaluates biological intervention strategies, and here the probiotics story takes center stage. Lactobacillus rhamnosus GG has been shown to ameliorate DON-induced intestinal damage in weaned piglets by enriching beneficial bacteria, and to protect against DON exposure by promoting butyrate production through gut microbiota modulation—consistent with independent findings that butyrate reduces DON-induced epithelial barrier dysfunction in pig jejunum organoid-derived monolayers. Bacillus velezensis mitigates intestinal inflammation and liver injury via microbiota modulation, Lactiplantibacillus plantarum JM113 alleviates mitochondrial dysfunction in the jejunum of broilers, and Lactobacillus rhamnosus MY-1 relieves oxidative stress, inflammation and dysbiosis in vivo and in vitro. The mechanisms are diverse: regulation of apoptosis, protection of tight junctions and mucus production, direct modulation of the MAPK, NF-κB and Nrf2 pathways, and release of bioactive metabolites. Some organisms go further, actually detoxifying DON—bacterial biotransformation to 3-epi-deoxynivalenol and de-epoxy-deoxynivalenol (DOM-1) reduces toxicity in piglets, and novel enzymatic routes, including a Bacillus subtilis glycosyltransferase that converts DON into a glucosylated metabolite, are being characterized.

Yet the authors are candid about the bottlenecks. The structures and toxicology of many DON degradation products remain unclear—detoxification that merely relocates the hazard is no solution at all. Probiotic strains show poor intestinal stability under real-world conditions, strong strain-to-strain specificity, and a persistent tendency for in vitro efficacy to overestimate what will happen in living animals. Early trials with Bacillus spore-based feed additives, for instance, failed to prevent DON absorption and toxicity in piglets. The review also notes that mycotoxins rarely occur alone: interactions between DON and co-contaminants such as zearalenone, fumonisin B1, enniatins and cereulide can be additive, synergistic or unexpectedly antagonistic, complicating risk assessment built on single-toxin studies.

The path forward, the authors argue, lies in mechanistic studies of combined effects—pairing DON with candidate intervention agents under physiologically realistic conditions, using organoid and co-culture models alongside in vivo work, and resolving the chemistry of biotransformation products before they are deployed. For a toxin that contaminates a substantial fraction of the global grain supply and that recent work links to low-dose inflammatory responses relevant to children, the stakes are considerable. What this review makes clear is that DON’s danger lies less in brute-force cytotoxicity than in its exploitation of the cell’s own communication networks—and that effective countermeasures will need to operate at the same systems level, restoring the balance of signaling pathways rather than simply binding or degrading a single molecule.

Subject of Research: Toxicological mechanisms and biological intervention strategies for the mycotoxin deoxynivalenol

Article Title: Deoxynivalenol-induced cellular signal transduction: research progress on toxicological effects, molecular mechanisms, and biological intervention strategies

Article References: Deoxynivalenol-induced cellular signal transduction: research progress on toxicological effects, molecular mechanisms, and biological intervention strategies. (n.d.). https://doi.org/10.1007/s11033-026-12894-5

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12894-5

Keywords: deoxynivalenol, mycotoxin, ribotoxic stress response, MAPK signaling, NF-κB, oxidative stress, ferroptosis, intestinal barrier, probiotics, gut microbiota, food safety, detoxification