Cold Atmospheric Plasma Promotes Anti-Inflammatory and Regenerative Responses in Oral Soft Tissue through Redox-Driven Mitochondrial Regulation

Cold atmospheric plasma (CAP) offers a promising therapeutic approach for controlling inflammation and stimulating soft-tissue regeneration within the oral cavity. In this study, human gingival fibroblasts (HGF-1) challenged with lipopolysaccharide (LPS) were treated with helium-based CAP to elucidate how redox-driven mitochondrial regulation mediates its biological effects. Optical emission spectroscopy and infrared thermography verified that the helium dielectric barrier discharge system generated a nonthermal, chemically reactive plasma plume rich in reactive oxygen and nitrogen species (RONS). Controlled CAP exposure transiently elevated intracellular hydrogen peroxide (H₂O₂) without inducing cytotoxicity, re-establishing redox equilibrium, and suppressing excessive oxidative signaling. This modulation attenuated LPS-induced NF-κB activation and reduced the secretion of IL-6, IL-1β, and TNF-α, while enhancing collagen I expression, cell migration, and proliferation, indicating a transition from an inflammatory to a regenerative phenotype. Mechanistically, CAP activated the PGC-1α/NRF-1/TFAM regulatory network, restoring mitochondrial membrane potential, decreasing mitochondrial ROS, and promoting biogenesis. These mitochondrial adaptations functioned as a mechanistic bridge, linking redox modulation to both anti-inflammatory suppression and regenerative activation. Catalase completely abolished these effects, confirming H₂O₂ as the central mediator. Therefore, CAP constitutes a redox-regulatory, nonpharmacological approach that integrates oxidative and mitochondrial signaling to resolve oral soft-tissue inflammation and promote functional regeneration.