ERK5 Signaling and Ferroptosis in Bone Homeostasis: Emerging Connections and Therapeutic Perspectives
- 1Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China
- 2Intelligent Orthopedic Industry Technology Center of Gansu Province, Orthopedic Clinical Medical Research Center, Lanzhou 730030, China
- 3The Second School of Clinical Medicine, Lanzhou University, Lanzhou 730030, China
Abstract
Bone homeostasis depends on coordinated activity among bone marrow mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. Disruption of this cellular network contributes to osteoporosis, impaired fracture repair, and other skeletal disorders, while redox stress and regulated cell-death programs increasingly appear to shape the behavior of these skeletal populations. Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and failure of antioxidant defenses. Preclinical studies indicate that ferroptotic injury can compromise osteogenic differentiation, osteoblast function, and osteocyte integrity; in osteoclasts, the biological effect is more model-dependent. Extracellular signal-regulated kinase 5 (ERK5/MAPK7) integrates mechanical, oxidative, inflammatory, and metabolic cues, but skeletal studies have reported divergent effects across genetic, pharmacological, developmental, and mechanically stimulated models. Direct evidence that ERK5 regulates ferroptosis in skeletal cells is still lacking. This review evaluates ferroptosis and ERK5 signaling as potentially interacting stress-response systems, separates established findings from indirect and hypothetical links, and examines how ERK5-dependent stress adaptation, mitochondrial regulation, and metabolic state may modify ferroptotic susceptibility. We propose that ERK5 may shift the threshold between adaptive survival and ferroptotic injury in a cell-, stress-, and disease-stage-dependent manner, providing a testable framework for skeletal degeneration and regeneration.
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BibTeX
@article{zhang2026erk5,
title = {{ERK5 Signaling and Ferroptosis in Bone Homeostasis: Emerging Connections and Therapeutic Perspectives}},
author = {Jiangying Zhang and Xiping Dou and Haochuan You and Xiuyuan Wang and Yixiang Zhao and Bin Geng and Yayi Xia},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101521},
url = {https://www.mdpi.com/2218-273X/16/10/1521},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ERK5 Signaling and Ferroptosis in Bone Homeostasis: Emerging Connections and Therapeutic Perspectives
AU - Jiangying Zhang
AU - Xiping Dou
AU - Haochuan You
AU - Xiuyuan Wang
AU - Yixiang Zhao
AU - Bin Geng
AU - Yayi Xia
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101521
UR - https://www.mdpi.com/2218-273X/16/10/1521
AB - Bone homeostasis depends on coordinated activity among bone marrow mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. Disruption of this cellular network contributes to osteoporosis, impaired fracture repair, and other skeletal disorders, while redox stress and regulated cell-death programs increasingly appear to shape the behavior of these skeletal populations. Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and failure of antioxidant defenses. Preclinical studies indicate that ferroptotic injury can compromise osteogenic differentiation, osteoblast function, and osteocyte integrity; in osteoclasts, the biological effect is more model-dependent. Extracellular signal-regulated kinase 5 (ERK5/MAPK7) integrates mechanical, oxidative, inflammatory, and metabolic cues, but skeletal studies have reported divergent effects across genetic, pharmacological, developmental, and mechanically stimulated models. Direct evidence that ERK5 regulates ferroptosis in skeletal cells is still lacking. This review evaluates ferroptosis and ERK5 signaling as potentially interacting stress-response systems, separates established findings from indirect and hypothetical links, and examines how ERK5-dependent stress adaptation, mitochondrial regulation, and metabolic state may modify ferroptotic susceptibility. We propose that ERK5 may shift the threshold between adaptive survival and ferroptotic injury in a cell-, stress-, and disease-stage-dependent manner, providing a testable framework for skeletal degeneration and regeneration.
SN - 2218-273X
ER -