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Peer-reviewedCC BY 4.0Advanced Science

Plasma Membrane Lipid Asymmetry Dynamically Regulates Passive Diffusion

  • Jieming Ping1,2
  • Wenliang Wang2
  • Jinnuo Xu2
  • Mengyun Yang2
  • Ning Wu1,2,3,4,5,6
6 affiliations
  1. 1Department of Immunology School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
  2. 2The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology Anhui Medical University Hefei China
  3. 3Innovative Institute of Tumor Immunity and Medicine (ITIM) Hefei China
  4. 4Cell Architecture Research Center Tongji Medical College Huazhong University of Science and Technology Wuhan China
  5. 5Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy Hefei China
  6. 6Inflammation and Immune Mediated Diseases Laboratory of Anhui Province Anhui Medical University Hefei China
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Abstract

Plasma membrane (PM) phospholipid asymmetry is a fundamental feature of eukaryotic cells that regulates signaling, trafficking, and cell fate. Whether it also controls passive diffusion across the PM remains unknown. Here, we show that phospholipid asymmetry is a critical determinant of PM permeability to hydrophobic molecules. Using genetic and biochemical approaches, we demonstrate that disruption of lipid asymmetry by the Ca2 +‐activated scramblase TMEM16F or apoptotic scramblase XKR8 profoundly alters the permeation and intracellular accumulation of diverse hydrophobic compounds, including widely used fluorescent probes, while preserving the barrier to membrane‐impermeable molecules. Lipid scrambling is sufficient to remodel membrane permeability to lipophilic molecules, alter membrane biophysical properties, and differentially affect their intracellular accumulation, suggesting selective regulation of passive diffusion rather than nonspecific membrane leakage. Physiological lipid scrambling during T cell activation was also accompanied by altered membrane permeability. Moreover, lipid asymmetry regulates the cellular entry of doxorubicin, 17β‐estradiol, and all‐trans retinoic acid. Together, our findings identify PM lipid asymmetry as a previously unrecognized regulator of membrane permeability and establish a link between membrane organization and molecular transport.

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Cite

BibTeXRIS
BibTeX
@article{ping2026plasma,
  title = {{Plasma Membrane Lipid Asymmetry Dynamically Regulates Passive Diffusion}},
  author = {Jieming Ping and Wenliang Wang and Jinnuo Xu and Mengyun Yang and Ning Wu},
  journal = {Advanced Science},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78435},
  url = {https://doi.org/10.1002/advs.78435},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Plasma Membrane Lipid Asymmetry Dynamically Regulates Passive Diffusion
AU  - Jieming Ping
AU  - Wenliang Wang
AU  - Jinnuo Xu
AU  - Mengyun Yang
AU  - Ning Wu
PY  - 2026
DA  - 2026/10/25
JO  - Advanced Science
DO  - 10.1002/advs.78435
UR  - https://doi.org/10.1002/advs.78435
AB  - Plasma membrane (PM) phospholipid asymmetry is a fundamental feature of eukaryotic cells that regulates signaling, trafficking, and cell fate. Whether it also controls passive diffusion across the PM remains unknown. Here, we show that phospholipid asymmetry is a critical determinant of PM permeability to hydrophobic molecules. Using genetic and biochemical approaches, we demonstrate that disruption of lipid asymmetry by the Ca2 +‐activated scramblase TMEM16F or apoptotic scramblase XKR8 profoundly alters the permeation and intracellular accumulation of diverse hydrophobic compounds, including widely used fluorescent probes, while preserving the barrier to membrane‐impermeable molecules. Lipid scrambling is sufficient to remodel membrane permeability to lipophilic molecules, alter membrane biophysical properties, and differentially affect their intracellular accumulation, suggesting selective regulation of passive diffusion rather than nonspecific membrane leakage. Physiological lipid scrambling during T cell activation was also accompanied by altered membrane permeability. Moreover, lipid asymmetry regulates the cellular entry of doxorubicin, 17β‐estradiol, and all‐trans retinoic acid. Together, our findings identify PM lipid asymmetry as a previously unrecognized regulator of membrane permeability and establish a link between membrane organization and molecular transport.
SN  - 2198-3844
ER  -