Recent advances in TMEM16F: structural plasticity, functional versatility, and implications for human diseases.

TMEM16F is a calcium-activated membrane protein that functions as both a non-selective ion channel and a phospholipid scramblase, linking intracellular Ca²⁺ signaling to dynamic regulation of plasma membrane lipid asymmetry. Recent studies have substantially advanced our understanding of TMEM16F structure and regulation, revealing pronounced conformational heterogeneity and allosteric mechanisms through which Ca²⁺, pH and membrane context coordinate its dual functions. Cell- and tissue-specific analyses indicate that TMEM16F-mediated membrane remodeling contributes to diverse physiological processes, including blood coagulation, cell-cell fusion, regulated cell death, immune responses, and neurodevelopment. Dysregulation of TMEM16F activity has been associated with a broad spectrum of pathological conditions, ranging from bleeding disorders and thromboinflammation to neurodegeneration, infection-associated tissue damage, and cancer. This review integrates recent structural, cellular and pathological insights to provide a comprehensive overview of TMEM16F biology, highlighting mechanisms underlying its dual functions and summarizing emerging evidence for its roles in health and disease.