Echinacoside improves antioxidant responses and angiogenesis through Parkin-MFN2-mediated mitophagy to promote diabetic wound healing

  • Free Radic Biol Med. 2026 Jul:250:436-452. doi: 10.1016/j.freeradbiomed.2026.04.012.
Zi Li  1 ,  Zhi Li  1 ,  Qiubo Li  2 ,  Ronghui Miao  1 ,  Yuchao Ma  1 ,  Silei Wei  2 ,  Junnan Mao  2 ,  Xuan Wang  1 ,  Xiangtao Zeng  2 ,  Yi Zhou  1 ,  Jingjing Ye  1 ,  Weidong Xia  3 ,  Cai Lin  4 ,  Cong Mao  5
Affiliations
  • 1. Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 2. Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Department of Burn and Wound Healing Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 3. Department of Burn and Wound Healing Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 4. Department of Burn and Wound Healing Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: [email protected].
  • 5. Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. Electronic address: [email protected].
PMID: 41962601 DOI: 10.1016/j.freeradbiomed.2026.04.012
Abstract

Due to complex immune and metabolic dysfunctions, diabetic wounds commonly suffer from Infection, oxidative stress, impaired angiogenesis, thereby leading to chronic non-healing lesions. Since current therapies remain insufficient, increasing attention has been directed toward Mitophagy, a key regulator of energy balance and stress responses, with mitochondrial dysfunction recognized as a critical driver of defective repair. In this study, we explored the therapeutic role of echinacoside (Ech), a phenylethanol glycoside from Echinacea, known for its potent antioxidant, anti-inflammatory, and pro-angiogenic properties, in promoting diabetic wound healing. Network pharmacology analysis was employed to identify the potential targets of Ech in diabetic condition. In vitro, under H2O2-induced oxidative stress, Ech mitigated the functional impairment of human umbilical vein endothelial cells (HUVECs), enhancing their proliferation, migration, angiogenesis, and antioxidant capacity. Mechanistically, Ech restored HUVECs function by activating Parkin-MFN2-mediated Mitophagy through ubiquitination and concurrently upregulated USP35 expression, which mitigated excessive Mitophagy. These effects were confirmed using the Parkin-dependent Mitophagy inhibitor cyclosporin A (CsA) and USP35-specific siRNA (siUSP35). In a diabetic mouse full-thickness cutaneous wound model, Ech treatment significantly activated Parkin-dependent Mitophagy, leading to enhanced neovascularization and Collagen deposition at wound site, thereby accelerated the healing process of diabetic wounds. Collectively, these findings identify Ech as a promising therapeutic agent for diabetic wound repair and provide mechanistic insights into its regulation of Mitophagy to improve antioxidant responses and angiogenesis, offering a foundation for the development of targeted treatment strategies.

Keywords
Angiogenesis; Diabetic wound; Echinacoside; Mitophagy.
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