TMEM63B as a dual-function mechanosensitive channel and lipid scramblase: structural insights, physiological roles, and pharmacological potential

TMEM63B, a member of the transmembrane channel/scramblase (TCS) superfamily, functions as both a mechanosensitive and osmosensitive ion channel and a lipid scramblase. Recent structural and functional studies have begun to reveal the molecular basis underlying these dual functions. In this review, we summarize the current understanding of TMEM63B, focusing on its structural architecture, channel and scramblase conformations, activation mechanisms, physiological roles and therapeutic potential. Importantly, the broad tissue distribution and disease-associated mutations of TMEM63B-linked to developmental epileptic encephalopathy, hemolytic anemia, placental dysfunction, pulmonary insufficiency, and intestinal barrier defects-underscore its emerging pharmacological relevance. We discuss the therapeutic opportunities and challenges in targeting TMEM63B, including allosteric modulation of its mechanosensitive gating, isoform- and tissue-selective strategies to mitigate on-target off-tissue toxicity, and the potential of biologics such as the agonistic antibody YN9303-24 for loss-of-function disorders. These insights provide a framework for understanding the mechanistic diversity of TCS proteins, their physiological significance, and their translational potential as a new class of druggable mechanosensitive targets.