2. Academic Validation
  3. RCN1 downregulation-driven endoplasmic reticulum stress impairs endothelial function and diabetic foot ulcer healing

RCN1 downregulation-driven endoplasmic reticulum stress impairs endothelial function and diabetic foot ulcer healing

  • Cell Mol Life Sci. 2025 Aug 25;82(1):318. doi: 10.1007/s00018-025-05814-6.
Zhiyan Weng # 1,  Xiaoyan Ren # 1,  Wanxin Lin 1,  Lifeng Zheng 2,  Renfu Weng 1,  Liangxiao Xie 3,  Fengying Zhao 1 4 5 6 7 8,  Sunjie Yan 9 10 11 12 13 14,  Ximei Shen 15 16 17 18 19 20
Affiliations

Affiliations

  • 1 Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong Road, Fuzhou, 350005, China.
  • 2 Department of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 3 Department of Endocrinology and Metabolism, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, 363000, China.
  • 4 Department of Endocrinology, First Affiliated Hospital, National Regional Medical Center, Binhai Campus, Fujian Medical University, Fuzhou, 350212, China.
  • 5 Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 6 Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 7 Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 8 Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 9 Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong Road, Fuzhou, 350005, China. fjyansunjie@163.com.
  • 10 Department of Endocrinology, First Affiliated Hospital, National Regional Medical Center, Binhai Campus, Fujian Medical University, Fuzhou, 350212, China. fjyansunjie@163.com.
  • 11 Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. fjyansunjie@163.com.
  • 12 Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. fjyansunjie@163.com.
  • 13 Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. fjyansunjie@163.com.
  • 14 Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. fjyansunjie@163.com.
  • 15 Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, 20 Cha Zhong Road, Fuzhou, 350005, China. niaoshe2006@163.com.
  • 16 Department of Endocrinology, First Affiliated Hospital, National Regional Medical Center, Binhai Campus, Fujian Medical University, Fuzhou, 350212, China. niaoshe2006@163.com.
  • 17 Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. niaoshe2006@163.com.
  • 18 Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. niaoshe2006@163.com.
  • 19 Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. niaoshe2006@163.com.
  • 20 Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. niaoshe2006@163.com.
  • # Contributed equally.
PMID: 40853392 DOI: 10.1007/s00018-025-05814-6
Abstract

Diabetic foot ulcers (DFUs) are a leading cause of disability and mortality, with endothelial dysfunction playing a key role in the development of non-healing ulcers. A primary driver of endothelial cell impairment in this context is endoplasmic reticulum (ER) stress, triggered by glycolipotoxicity, though the underlying mechanisms are not fully understood. In this study, we observed that diabetic mice displayed poor ulcer healing associated with reduced angiogenesis and downregulated Reticulocalbin 1 (RCN1) expression. Proteomic analysis in human umbilical vein endothelial cells (HUVECs) identified a strong link between RCN1 and the damaging effects of glycolipotoxicity on endothelial cell function, leading to impaired tubule formation, reduced migratory capacity, and increased Apoptosis in endothelial cells. Mechanistic RNA Sequencing analysis highlighted a significant role for RCN1 in regulating ER function. RCN1 overexpression alleviated ER stress by reducing Protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylation and C/EBP homologous protein (CHOP) expression, both induced by glycolipotoxicity or Thapsigargin (TG), while RCN1 silencing intensified these effects. Additionally, TRIM11-mediated ubiquitination, influenced by glycolipotoxicity, regulated RCN1 stability, specifically promoting angiogenesis through RCN1 modulation. RCN1 overexpression accelerated ulcer healing in diabetic mice by suppressing ER stress proteins and enhancing angiogenesis, whereas RCN1 inhibition further delayed ulcer healing. In human DFU samples, proteomic analysis revealed that low RCN1 levels were linked to disrupted ER functional proteins, with RCN1 serum levels decreasing as diabetes progressed to DFU. Following surgical debridement treatment, RCN1 levels increased in patients with improved DFU healing outcomes. These findings suggest that ER stress, initiated by RCN1 inhibition in response to glycolipotoxicity, leads to endothelial dysfunction and Apoptosis, ultimately contributing to the non-healing of DFUs.

Keywords

Apoptosis; Diabetic foot ulcer; Endoplasmic reticulum stress; Endothelial cells; Endothelial function; RCN1.

Figures
Products