2. Academic Validation
  3. Piezo1-Mediated Ferroptosis Delays Wound Healing in Aging Mice by Regulating the Transcriptional Activity of SLC7A11 through Activating Transcription Factor 3

Piezo1-Mediated Ferroptosis Delays Wound Healing in Aging Mice by Regulating the Transcriptional Activity of SLC7A11 through Activating Transcription Factor 3

  • Research (Wash D C). 2025 Jun 3:8:0718. doi: 10.34133/research.0718.
Chen Jin 1 2 3,  Du-Piao Zhang 1 2 3,  Zhen Lin 4,  Yu-Zhe Lin 3,  Yi-Feng Shi 3,  Xiao-Yu Dong 1 2,  Meng-Qi Jin 1 2,  Fu-Qiang Song 2,  Si-Ting Du 2,  Yan-Zhen Feng 2,  Lin-Yuan Jiang 2,  Xiao-Qiong Jiang 1 2,  Abdullah Al Mamun 5,  Zi-Miao Chen 1,  Jian Wang 1,  Keqing Shi 1,  Ren-Wen Wan 6,  Zhi-Wen Luo 6,  Zheng-Lin Li 2,  Lei Yang 3,  Jian Xiao 1 2 3
Affiliations

Affiliations

  • 1 Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China.
  • 2 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3 Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
  • 4 Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 5 Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China.
  • 6 Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200000, China.
PMID: 40463502 DOI: 10.34133/research.0718
Abstract

Ferroptosis plays a role in wound healing during the maturation of senescent endothelial cells. This study explores the modulation of Ferroptosis in senescent human umbilical vein endothelial cells (HUVECs) and wound-healing processes by Piezo1 activation at the molecular, cellular, and tissue levels. Elevated Piezo1 expression was observed in HUVECs treated with the senescence inducer doxorubicin (Doxo) and the Ferroptosis inducer erastin and in aged wound tissue. Pharmacological inhibition or knockdown of Piezo1 protected senescent HUVECs and aged wound tissue from Ferroptosis. Additionally, Piezo1 channel activity was found to promote Ferroptosis in senescent HUVECs by increasing intracellular CA2+ levels. The calmodulin-dependent kinase II (CaMKII)/activating transcription factor 3 (ATF3)/SLC7A11 signaling axis was activated upon stimulation with erastin and Doxo, driving Piezo1-induced Ferroptosis. CaMKII directly interacted with ATF3, which could be modulated through Piezo1 channel regulation. Notably, Piezo1 knockout mice or adeno-associated virus 9-mediated silencing of ATF3 attenuated Ferroptosis in senescent cells and accelerated wound repair. Mechanistically, both genetic and pharmacological inhibition of Piezo1 promoted wound healing in aged tissues and regulated Ferroptosis in senescent HUVECs through the CaMKII/ATF3/SLC7A11 pathway. In conclusion, these findings suggest that targeting Piezo1-mediated Ferroptosis in senescent HUVECs offers a promising therapeutic approach for improving wound healing in the elderly.

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