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Mfsd2a is important for maintaining epidermal homeostasis.

Bernice H Wong1, Kunal Mishra1,2, Cheen Fei Chin1

  • 1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.

Proceedings of the National Academy of Sciences of the United States of America
|February 19, 2026
PubMed
Summary

Mfsd2a, a transporter, is crucial for skin barrier function by enabling keratinocytes to uptake essential lipids. Its deficiency causes dermatitis, highlighting its role in maintaining skin health and differentiation.

Keywords:
fatty acidsmetabolismphospholipidskintransporters

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Area of Science:

  • Dermatology
  • Cell Biology
  • Biochemistry

Background:

  • The skin epidermis relies on external linoleate for acylceramide synthesis, vital for barrier function.
  • Disrupted skin barriers are linked to atopic dermatitis and psoriasis.
  • Keratinocytes in the epidermis require phosphatidylcholine for lamellar body secretion, but uptake mechanisms are unclear.

Purpose of the Study:

  • To investigate the role of Mfsd2a, a lysophosphatidylcholine transporter, in epidermal lipid acquisition and skin barrier maintenance.
  • To elucidate the mechanisms by which keratinocytes obtain phospholipids for barrier repair and function.

Main Methods:

  • Demonstrated Mfsd2a expression in keratinocytes and its role in lysophosphatidylcholine (LPC) uptake using a fluorescent probe.
  • Created epidermal-specific Mfsd2a-deficient mice and performed inducible deletion in primary mouse keratinocytes.
  • Conducted untargeted lipidomic analysis and functional studies with primary human keratinocytes.

Main Results:

  • Mfsd2a deficiency in mice led to dermatitis and impaired epidermal desquamation.
  • Deletion of Mfsd2a in keratinocytes inhibited epidermal stratification in vitro.
  • Lipidomic analysis revealed reduced linoleic acid in phosphatidylcholine and triglycerides in Mfsd2a-deficient epidermis.
  • LPC-oleate and LPC-linoleate promoted keratinocyte differentiation dependently on Mfsd2a.

Conclusions:

  • Mfsd2a is predominantly expressed in keratinocytes and mediates the uptake of plasma-derived LPC.
  • This Mfsd2a-dependent LPC uptake is essential for maintaining epidermal phosphatidylcholine levels.
  • The findings identify a critical pathway for keratinocyte differentiation and skin barrier integrity.