Guang Chenpi Extract as a Multifunctional Phytotherapeutic: Enhanced Effects with Ergothioneine and Polydeoxyribonucleotide on Redox Homeostasis and Tissue Resilience

Background/Objectives: Guang Chenpi, the aged pericarp of Citrus reticulata ‘Chachi’, is a traditional Chinese medicinal food with documented health benefits. This study aimed to systematically evaluate the multifaceted bioactivity of a standardized Guang Chenpi extract (GCE), both alone and in combination with ergothioneine (EGT) and polydeoxyribonucleotide (PDRN), using in vitro and in vivo models. Methods: GCE quality was characterized by LC-MS/MS. Combination regimens of GCE with EGT or PDRN were assessed in UVB-irradiated 3D MelaKutis® skin tissue for ROS levels, antioxidation defense markers (NNT, GSH-PX1), and melanocyte protein (Pmel17). In zebrafish, GCE was evaluated for toxicity, antioxidant activity, tail fin regeneration, skin barrier protection, melanogenesis inhibition, and expression of collagen (col1a1a, col1a1b, and col1a2) and elastin (elna) genes. Results: In 3D skin models, GCE combined with EGT or PDRN significantly enhanced antioxidant defenses (NNT increased by 113–186%; GSH-PX1 by 173–231%), reduced ROS by 46.27–57.76%, and decreased melanocyte protein (Pmel17) by 23.44–44.27%. In zebrafish, GCE showed low toxicity (≤0.63 mg/mL) and exhibited dose-dependent antioxidant activity (ROS reduction: 27.57–61.85%), enhanced tail fin regeneration (11.35–27.84%), and strengthened skin barrier function (65.20–89.32% protection). GCE also upregulated collagen and elastin gene expression, improved blood circulation, and suppressed melanogenesis. Conclusions: GCE is a promising multifunctional natural ingredient with significant antioxidant, regenerative, and skin-protective properties. Its combination with EGT or PDRN results in enhanced protective effects against UVB-induced skin damage, supporting its potential use in advanced pharmaceutical and cosmeceutical formulations.