Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and in children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated to this process. Here, we show that loss of the mechanosensitive channels TMEM63A and TMEM63B (TMEM63A/B) resulted in atelectasis and respiratory failure in mice due to a deficit of surfactant secretion. TMEM63A/B were predominantly localized at the limiting membrane of the lamellar body (LB), a lysosome-related organelle that stores pulmonary surfactant and ATP in AT2 cells. Activation of TMEM63A/B channels during cell stretch facilitated the release of surfactant and ATP from LBs fused with the plasma membrane. The released ATP evoked Ca²⁺ signaling in AT2 cells and potentiated exocytic fusion of more LBs. Our study uncovered a vital physiological function of TMEM63 mechanosensitive channels in preparing the lungs for the first breath at birth and maintaining respiration throughout life.

Sphingosine-1-phosphate (S1P) is an important sphingolipid molecule involved in regulating cardiovascular functions in physiological and pathological conditions by binding and activating the three G protein-coupled receptors (S1PR1, S1PR2, and S1PR3) expressed in endothelial and smooth muscle cells, as well as cardiomyocytes and fibroblasts. It exerts its actions through various downstream signaling pathways mediating cell proliferation, migration, differentiation, and apoptosis. S1P is essential for the development of the cardiovascular system, and abnormal S1P content in the circulation is involved in the pathogenesis of cardiovascular disorders. This article reviews the effects of S1P on cardiovascular function and signaling mechanisms in different cell types in the heart and blood vessels under diseased conditions. Finally, we look forward to more clinical findings with approved S1PR modulators and the development of S1P-based therapies for cardiovascular diseases.

Phospholipids are asymmetrically distributed across mammalian plasma membrane. The function of P4-ATPases is to maintain the abundance of phosphatidylserine (PS) and phosphatidylethanolamine (PE) in the inner leaflet as lipid flippases. Transmembrane protein 30A (TMEM30A, also named CDC50A), as an essential β subunit of most P4-ATPases, facilitates their transport and functions. With TMEM30A knockout mice or cell lines, it is found that the loss of TMEM30A has huge influences on the survival of mice and cells because of PS exposure-triggered apoptosis signaling. TMEM30A is a promising target for drug discovery due to its significant roles in various systems and diseases. In this review, we summarize the functions of TMEM30A in different systems, present current understanding of the protein structures and mechanisms of TMEM30A-P4-ATPase complexes, and discuss how these fundamental aspects of TMEM30A may be applied to disease treatment.

Atherosclerosis, a chronic inflammatory–metabolic disorder, remains a leading cause of cardiovascular morbidity worldwide. This review explores the emerging paradigm of nanomedicine‐based targeting of macrophage immunometabolic reprogramming as a potentially transformative strategy for atherosclerosis treatment. We emphasize innovative approaches such as stimulus–responsive nanocarriers (e.g., pH‐, reactive oxygen species‐, or enzyme‐activated systems) for spatiotemporal drug delivery and metabolic modulation within plaques, and nanoplatforms for delivering genetic regulators (e.g., small interfering RNA or microRNA) for precise manipulation of key metabolic targets, including 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (glycolysis) and ATP‐binding cassette A1 (cholesterol efflux). Despite promising preclinical outcomes, clinical translation faces substantial challenges, including optimizing nanocarrier biocompatibility, achieving subtype‐specific targeting amid macrophage heterogeneity, and resolving scalability and standardization issues. Future advancements will require interdisciplinary collaboration integrating immunometabolism, materials science, and artificial intelligence to develop next‐generation nanotherapeutics, coupled with robust clinical validation to facilitate their translation into personalized therapies for atherosclerosis.