Intracellular ROS

Overview

Intracellular ROS refers to reactive oxygen species generated within cells, including species such as superoxide, hydrogen peroxide, and related oxidants that participate in redox signaling but can also drive oxidative damage when produced in excess. In normal physiology, intracellular ROS help regulate processes such as proliferation, differentiation, immune signaling, and stress responses. Their levels are tightly controlled by antioxidant systems including glutathione, superoxide dismutase, catalase, and glutathione peroxidase.

In biomedical research, intracellular ROS is commonly treated as a mechanistic readout and therapeutic target because many diseases involve redox imbalance. Elevated intracellular ROS is associated with apoptosis, ferroptosis, mitochondrial dysfunction, DNA damage, inflammation, senescence, and tissue injury, while ROS scavenging or suppression is often linked to cytoprotection and restoration of redox homeostasis. Conversely, many anticancer and antimicrobial strategies intentionally increase intracellular ROS to overwhelm tumor or pathogen defenses, often in combination with photochemotherapy, cuproptosis, ferroptosis, or chemotherapy.

Focus of Latest Publications

Recent studies have used intracellular ROS as both a biomarker of cellular stress and a functional mediator of treatment response across cancer, infection, inflammation, wound repair, neurodegeneration, and metabolic disease.

Several anticancer studies reported that treatment increased intracellular ROS as part of the cytotoxic mechanism. A novel alkyl pyridinium derivative in triple-negative breast cancer cells induced apoptosis with caspase-3/7 activation, elevated ROS, and mitochondrial membrane depolarization. berberine chloride similarly increased intracellular ROS and loss of mitochondrial membrane potential in MDA-MB-231 and 4T1 breast cancer cells, consistent with apoptosis. Santamarine synergized with cisplatin in oral cancer cells through a ROS/JNK axis, enhancing oxidative stress, apoptosis, and DNA damage. Vitamin D3 and K2-loaded keratin nanoparticles were reported to inhibit breast cancer cell growth, with the K2-loaded formulation inducing intracellular ROS generation. Quinoa bran triterpenoids triggered lethal ROS accumulation in colorectal cancer cells, leading to mitochondrial dysfunction and caspase-dependent apoptosis. sorafenib combined with Atorvastatin amplified ROS, malondialdehyde, and membrane depolarization in colorectal cancer models, supporting a mixed apoptosis/ferroptosis mechanism. In another colorectal cancer-related study, artemisinin treatment reversed lipid ROS production and inflammatory changes, indicating redox modulation as part of its effect.

ROS generation was also central to ferroptosis-oriented and metal-based nanotherapeutic strategies. A cantharidin liposome system increased intracellular Fe2+ levels, inhibited the SLC7A11/GSH/GPX4 antioxidant axis, and promoted ROS production in tumor cells, thereby inducing ferroptosis. A hyaluronic acid-targeted copper/manganese nanobioreactor with H2O2 self-supply was designed for ROS-based dynamic therapy to induce ferroptosis and apoptosis in hepatocellular carcinoma. A copper-iodide nanoparticle system generated ROS under low-dose X-ray irradiation to drive cell death, and a hemin-based polymer nanomicelle produced intracellular ROS from molecular hemin to mediate ferroptosis. A glutathione-depleting mitochondria-targeting nanodrug was developed because tumor GSH can neutralize PDT-generated ROS and blunt copper-mediated killing, highlighting the importance of intracellular redox buffering in therapy resistance. Similarly, a ROS storm generated by ultrasound-responsive biomimetic nanocarriers was used to disrupt triple-negative breast cancer immunosuppression through coordinated apoptosis, ferroptosis, and senescence.

Other studies focused on suppressing intracellular ROS to protect tissues or restore homeostasis. quercetin-loaded cellulose nanocrystals scavenged ROS, enhanced mitochondrial antioxidant defense through SOD2 translocation and activation, and inhibited NF-κB signaling in rosacea-related models. A biomimetic nanoparticle for sepsis efficiently scavenged ROS and suppressed LPS-induced TNF-α, IL-6, and IL-1β secretion through inhibition of TLR4/NF-κB signaling. In diabetic wound healing, a self-healing hydrogel containing carboxymethyl chitosan and oxidized bacterial nanocellulose reduced intracellular ROS and improved collagen synthesis, fibroblast and keratinocyte proliferation, and glucose handling. A PEG/metformin hydrogel restored mitochondrial membrane potential, reduced ROS accumulation, and lowered Hif-1α and IL-1β in diabetic foot ulcer models. Pirfenidone reduced renal oxidative stress and mitochondrial dysfunction in diabetic kidney disease, while myricetin lowered intracellular ROS and malondialdehyde and improved the GSH/GSSG ratio in vascular calcification models. Ghrelin attenuated astrocyte mitochondrial damage in an Alzheimer’s disease-related model by reducing ROS and improving mitochondrial membrane potential and respiratory complex activity.

Intracellular ROS was also linked to inflammatory and senescence phenotypes. Ambient NO2 exposure induced premature pulmonary senescence with elevated ROS, β-galactosidase activity, and G1 arrest in HBE cells, involving the ROS-DRG1/CDK5 axis. In skin and intestinal models, probiotic strains and probiotic extracellular vesicles reduced intracellular ROS and supported barrier function, mitochondrial respiration, and redox homeostasis. In skin photoaging, avenanthramide C suppressed UVB-induced ROS generation and inflammatory progression. In spinal cord injury, excessive ROS was described as part of a hostile microenvironment that perpetuates inflammation and secondary injury. In atherosclerotic plaque therapy, ultrasound-triggered ROS generation induced foam cell apoptosis and promoted plaque regression.

ROS-responsive materials and delivery systems were a major theme across the studies. ROS-responsive hydrogels, nanogels, micelles, microneedles, and nanocomposites were engineered using hyaluronan sodium, polydopamine, carboxymethyl chitosan, lignin@Fe3O4 nanoclusters, and related platforms to either release drugs in oxidative environments or scavenge excess oxidants. Examples included ROS-responsive phenylboronic acid-modified hyaluronic acid nanogels for diabetic wound healing, a ROS-responsive hydrogel for postoperative abdominal adhesion prevention, and ROS-responsive polydopamine-rosmarinic acid nanotherapeutics for ferroptosis-driven Parkinson’s disease modulation in Caenorhabditis elegans. A ROS-responsive polyprodrug co-delivery system for curcumin and cinnamaldehyde was designed to disrupt tumor redox homeostasis, and a ROS-responsive micelle probe was used in bladder cancer-derived extracellular vesicle detection. These studies collectively emphasize that intracellular ROS can be both a trigger for smart release and a therapeutic vulnerability.

Several publications also examined intracellular ROS in infectious disease and host-pathogen interactions. Lopinavir/ritonavir treatment in Leishmania donovani induced oxidative imbalance with increased ROS, depleted intracellular glutathione, and enhanced lipid peroxidation. Probiotic strains reduced intracellular ROS and nitric oxide in Salmonella-challenged epithelial and immune cell models, while food-derived biohybrid probiotic extracellular vesicles scavenged ROS in inflammatory bowel disease-related systems. In infected wound models, photocatalytic antimicrobial therapy generated ROS under illumination to achieve broad-spectrum sterilization, showing how ROS can be deliberately exploited against microbes.

Across these studies, intracellular ROS repeatedly served as a mechanistic bridge connecting mitochondrial dysfunction, antioxidant depletion, lipid peroxidation, apoptosis, ferroptosis, pyroptosis, senescence, and inflammatory signaling. The recurring involvement of pathways such as Nrf2/GPX4, SLC7A11/GSH, NF-κB, JNK, TGF-β1/Smad, and PI3K/AKT/HIF-1α underscores the central role of redox biology in disease progression and therapeutic design.

Key Publications

• Jun Novel anticancer alkyl pyridinium derivative exhibits antiproliferative activity via G0/G1 cell cycle arrest and apoptosis activation in triple-negative breast cancer cells. (Bioorganic & medicinal chemistry, 2026, PMID 41881862): "Flow cytometry assays confirmed that Compound 2 induces apoptosis as the primary mode of cell death, characterized by caspase-3/7 activation, elevated reactive oxygen species (ROS), and mitochondrial membrane depolarization."
• Jun Synthesis and evaluation of new 2-substituted anthra[2,3-b]furan-5,10-diones: tumor cell apoptosis through DNA binding and topoisomerases inhibition. (Bioorganic & medicinal chemistry, 2026, PMID 41905253): "None of the tested compounds generated significant reactive oxygen species, suggesting low oxidative stress and potentially reduced cardiotoxicity."
• Jun Lopinavir targets Leishmania topoisomerase I and its combination with Ritonavir exhibits enhanced antileishmanial efficacy in clinical isolates of Leishmania donovani. (Acta tropica, 2026, PMID 41946389): "At the cellular level, LPV-RTV treatment induces an oxidative imbalance characterized by increased reactive oxygen species generation, depletion of intracellular glutathione, and enhanced lipid accumulation and lipid peroxidation."
• Jun Cancer cell membrane and iRGD peptide co-modified cantharidin liposomes for targeted therapy and immunotherapy of triple-negative breast cancer. (Free radical biology & medicine, 2026, PMID 41812835): "This nanomedicine significantly increased intracellular Fe2+ levels, inhibited the solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 (SLC7A11/GSH/GPX4) antioxidant axis, and remarkably promoted the production of reactive oxygen species (ROS) in tumor cells, thereby inducing ferroptosis."
• Jun Hyaluronic acid-based reactive oxygen species responsive nanocomposite hydrogel for sequential drug delivery and effective prevention of postoperative abdominal adhesions. (Carbohydrate polymers, 2026, PMID 41943370): "Sustained inflammation with excessive reactive oxygen species (ROS) production and subsequent peritoneal mesothelial cells (PMCs)-mesenchymal transition (MMT) are key events driving PAA formation."
• Jun A self-healing, pH/glucose-responsive carboxymethyl chitosan and oxidized bacterial nanocellulose hydrogel for insulin and taurine delivery in diabetic wound healing. (Carbohydrate polymers, 2026, PMID 41943357): "In vitro, CPOPI+T enhanced glucose consumption by reversing insulin resistance, reduced intracellular ROS, increased collagen synthesis by 30%, promoted fibroblast and keratinocyte proliferation (165.87%±2.93%)."
• Jun A biomimetic nanoparticle for the treatment of sepsis via anti-inflammatory, antioxidant, and anticoagulant mechanisms. (European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2026, PMID 41990977): "In vitro, mPDA-Que@PM exhibited efficient ROS scavenging, significantly suppressed LPS-induced secretion of TNF-α, IL-6, and IL-1β, and inhibited the TLR4/NF-κB signaling pathway."
• Jun Stimuli-responsive copper-iodide nanoparticles for low-dose X-ray-induced photodynamic therapy and enhanced cuproptosis. (Acta biomaterialia, 2026, PMID 41990934): "The low-dose X-PDT process first generated reactive oxygen species to induce cell death."
• Jun Quercetin-loaded cellulose nanocrystals for targeted redox modulation and inflammation control in rosacea therapy via the SOD2-NF-κB pathway. (International journal of biological macromolecules, 2026, PMID 42106045): "Mechanistically, QL-CNC enhanced mitochondrial antioxidant defense by facilitating SOD2 translocation and activation, effectively scavenged ROS, and inhibited NF-κB activation-as indicated by reduced p65 phosphorylation and nuclear translocation."
• Jun Glutathione-depleting mitochondria-targeting nanodrugs for stress amplification and immune activation via synergistic photodynamic therapy and cuproptosis. (Acta biomaterialia, 2026, PMID 42002062): "However, tumors often overexpress glutathione (GSH), which neutralizes reactive oxygen species generated by PDT and blocks the cancer-killing effects of copper, thus compromising both therapeutic modalities."