ERK5 Signaling and Ferroptosis in Bone Homeostasis: Emerging Connections and Therapeutic Perspectives

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.