Targeting ferroptosis in osteoporosis: mechanisms and natural products therapies

Osteoporosis (OP) persists as the principal contributor to the global disease burden. OP is defined by reduced bone mass and impaired bone microarchitecture, thereby weakening bone strength and elevating fracture risk. Imbalanced bone remodeling is the major pathological mechanism of OP, in which osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation. Iron serves as a vital micronutrient for numerous biochemical activities and is essential for many cellular processes. Ferroptosis is an iron-dependent form of modulated cell death with unique traits, including disrupted iron balance, compromised antioxidant defenses, and aberrant lipid peroxidation. Ferroptosis participates in various physiological and pathological processes, and its role in bone-related diseases, particularly OP, is increasingly being explored. Hence, a systematic examination of the mechanisms modulating ferroptosis in OP is imperative to pinpoint potential therapeutic targets and innovate novel therapeutic and/or preventive strategies. The agents currently used to treat OP have numerous side effects, prompting increased research on natural compounds for OP treatment. This review systematically summarizes the key features and modulation mechanisms of ferroptosis based on the latest research advances, and explores its pathogenic implications and therapeutic opportunities in OP. Additionally, we also discussed investigations of natural products in vitro and in vivo to prevent OP by interfering with ferroptosis.