The therapeutic potential of Piezo1 channel-mediated ferroptosis and its inhibitor

Piezo1 is a mechanically activated, non-selective cation channel characterized by its exquisite sensitivity to membrane tension and high permeability to calcium(Ca²⁺⁾, enabling the conversion of mechanical stimuli into intracellular signaling events. Activation of Piezo1 leads to Ca²⁺ influx, which initiates iron metabolism reprogramming-including transferrin receptor 1(TfR1)-dependent iron uptake, divalent metal transporter 1(DMT1)-mediated iron transport, and Nuclear Receptor Coactivator 4(NCOA4)-regulated ferritinophagy-thereby promoting the accumulation of reactive oxygen species (ROS) and lipid peroxidation. Ultimately, these events culminate in ferroptosis by suppressing glutathione peroxidase 4 (GPX4) activity. The "mechanical force-Piezo1-Ca²⁺-iron/lipid metabolism" axis establishes mechanical stress as a pivotal upstream regulator of ferroptosis. This axis facilitates the functional integration of mechanotransduction into inflammatory mediator production, vascular and extracellular matrix(ECM) remodeling, and metabolic reprogramming. Furthermore, this signaling pathway exerts context-dependent pathogenic or protective effects across diverse pathological conditions, including musculoskeletal degeneration, ischemia-reperfusion injury, inflammatory bowel disease, neurovascular disorders, and cancer. This review provides a comprehensive overview of the molecular mechanisms and clinical evidence governing Piezo1-mediated ferroptosis. We summarize current pharmacological and genetic interventions for its inhibition-along with associated limitations such as selectivity and pharmacokinetic challenges-and explores interventions targeting the channel itself, Ca²⁺signaling, and downstream ferroptotic processes, including iron chelation, lipid peroxidation suppression, and preservation of the GPX4/coenzyme Q10 (CoQ10) axis. Furthermore, the potential for integrating these interventions with established therapeutic modalities is also discussed. A profound understanding of the druggability and context-dependent dynamics of the Piezo1-ferroptosis axis is expected to facilitate the discovery of novel therapeutic targets and combinatorial regimens for the precision management of mechanosensitive diseases.