Editorial on Special Collection in Contact : Lipid Transfer Proteins: From Molecular Mechanisms to Functional Validation

Interest in lipid transfer proteins (LTPs) began in the 60's and gained momentum when an alternative to vesicular lipid transport pathways was proposed (Urbani and Simoni, 1990; Zilversmit, 1984). However, studies describing the mechanisms of action, the organization, and the regulatory properties of LTPs appeared only recently. Now we know that many aspects of inter-organelle trafficking of membrane lipids are mediated by LTPs (Reinisch and Prinz, 2021; Wong et al., 2019). These proteins feature hydrophobic cavities or grooves that enable the rapid and often selective transport of lipids through the cytosol, and they are frequently concentrated at membrane contact sites. LTPs are essential for regulating the lipid composition of organelle membranes, either by quantitatively adjusting bulk lipid balance or by qualitatively promoting lipid conversion through metabolic enzymes, a process referred to as metabolic channeling (Hanada, 2024). In addition, their involvement in human diseases, ranging from cancer and neurodegenerative disorders to viral infections (Avula et al., 2021; Mishra et al., 2024; Peretti et al., 2020), suggests they play essential roles in cellular homeostasis. This collection, which includes three original research articles and four reviews, offers new perspectives on LTPs, from their molecular mechanisms and evolution to their functional roles in lipid regulation and their implications in disease.

Featuring original research, Singh et al. highlighted the evolutionary history of oxysterol-binding proteins (OSBPs), one of the best-studied LTP families (Singh et al., 2023). Their findings showed how OSBPs have evolved across fungi and animals, providing a deeper understanding of their functional diversity and essential role in lipid trafficking. The impact of OSBP and OSBP-related proteins (ORPs) in lipid homeostatic regulation was further explored in two studies from the Hammond's group. Doyle et al. revealed that OSBP does more than just exchange lipids—it actively controls Golgi phosphatidylinositol 4-phosphate (PI4P) levels, playing a key role in membrane organization and signaling in this organelle (Doyle, Timple et al., 2024). Moreover, by directing the PI4P-phosphatase SAC1 to mitochondria, they demonstrated that an LTP not restricted to contact sites—such as ORP2—can play a crucial role in PM PI4P turnover, thereby enhancing our understanding of lipid regulation across organelles (Doyle, Rectenwald et al., 2024).

Ceramide transport is another critical process for which LTPs stand out. Clausmeyer and Fröhlich reviewed mechanisms of non-vesicular ceramide transport between the ER and Golgi, revealing the complexity and importance of ceramide transfer proteins, in mammalian and yeast cells, to support sphingolipid metabolism and maintain cell signaling (Clausmeyer and Fröhlich, 2023). Further exploration of ceramide transport by Mizuike and Hanada described the function of DGARM at the ER-distal Golgi interface (Mizuike and Hanada, 2024). This protein, by interacting with the PI 4-kinase PI4KB, is essential for generating PI4P pools that facilitate ceramide transfer, illustrating how the creation of specialized membrane domains guides key lipid metabolic pathways. Finaly, Corbalan et al. discussed Arv1, a highly conserved protein proposed to regulate lipid asymmetry at the ER, thereby influencing lipid trafficking and membrane dynamics (Corbalan et al., 2025). Arv1's role in lipid homeostasis, along with its connection to diseases such as encephalopathy and neuronal degeneration, underlines its critical importance for maintaining proper cellular functions.

Last but not least, Ching et al. presented an original review highlighting the power of cryo-electron microscopy (cryo-EM) in unveiling the intricate architecture of membrane contact sites (Ching et al., 2024). Notably, they described the various applications of cryo-EM that have led to a better understanding of how LTPs interact with these specific membrane regions, offering valuable structural insights into their roles in cellular organization.

The growing body of research on LTPs has brought us closer to defining their molecular mechanisms and validating their roles in cellular functions. As we continue to unravel their complexities, we are uncovering new insights into how they sustain cell activity and their potential as therapeutic targets in diseases linked to lipid dysregulation.