Targeting the Angiotensin II/AT1R Pathway and Reactive Oxygen Species to Mitigate Oral Mucositis: Mechanistic Insights and Therapeutic Evidence

Oral mucositis (OM) is a common, severe, and dose-limiting toxicity of radiotherapy and chemotherapy, particularly in patients with head and neck malignancies or those undergoing hematopoietic stem cell transplantation. Affecting up to 80–100% of irradiated patients and approximately 40% of those receiving conventional chemotherapy, OM is characterized by painful inflammation and ulceration of the oral mucosa, leading to impaired nutrition, increased infection risk, prolonged hospitalization, life-long dental disease, treatment interruptions, and substantial healthcare costs. Despite its high prevalence and clinical burden, effective preventive and therapeutic options for OM remain limited. At the molecular level, OM pathogenesis is initiated by excessive generation of reactive oxygen species (ROS) resulting from radiolysis of water during radiation exposure and metabolic stress induced by cytotoxic chemotherapy. These ROS drive oxidative stress, DNA damage, lipid peroxidation, activation of proinflammatory transcription factors within epithelial and immune cells (macrophages, neutrophils) such as NF-κB, and amplification of cytokine signaling, culminating in epithelial barrier breakdown and ulceration. Emerging evidence suggests that the angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) axis may further exacerbate mucosal injury by stimulating NADPH oxidase (NOX)–dependent ROS production, thereby amplifying redox imbalance and inflammatory signaling. This review synthesizes current understanding of oxidative stress and the Ang II/AT1R–NOX pathway in mucositis pathobiology and evaluates therapeutic strategies targeting these mechanisms. We highlight preclinical evidence supporting the antioxidant Tempol, a superoxide dismutase mimetic that scavenges ROS, and angiotensin receptor blockers (ARBs), which attenuate upstream NOX activation. We propose a dual-targeting model in which concurrent suppression of ROS generation and neutralization of accumulated oxidants may more effectively mitigate oral mucosal injury than single-pathway interventions. Collectively, targeting oxidative stress and its upstream amplifiers represents a promising, mechanism-based approach for preventing and treating oral mucositis. Further mechanistic studies and well-designed clinical trials are warranted to validate this strategy and translate these insights into improved supportive care for patients undergoing mucosal toxic cancer therapies.