Scratching the Surface: Lipidomic Profiling of the Stratum Corneum in the Search for Pruritogens in Cholestatic Liver Diseases

Pruritus is a debilitating symptom frequently affecting patients with cholestatic liver disease, often resistant to conventional antipruritic therapies. The pathogenesis of cholestatic pruritus (CP) is multifactorial, implicating not only bile acids but also a complex array of other potential pruritogenic mediators and neural signaling pathways. Identification of the exact pruritogen has been elusive, and gaps remain in understanding the pathogenesis of pruritus, so developing targeted treatments is critical. The stratum corneum (SC), the outermost lipid-rich layer of the skin, may act as a reservoir for circulating pruritogens, offering a novel window to explore the pathogenesis of CP. Recent advancements in lipidomics and non-invasive tape stripping have enabled detailed profiling of SC lipid alterations in disease states. In this review, we synthesize the current understanding of CP and its candidate pruritogens and describe state-of-the-art approaches for SC lipid analysis, combining tape stripping to sample the skin surface with mass spectrometry-based lipidomics. Finally, we summarize cutaneous molecular findings and discuss how these techniques are facilitating biomarker discovery and informing therapeutic development. This review discusses the paradigm shift from a single-molecule perspective to a more integrated view of CP as a product of complex mediator interactions and highlights the potential of SC profiling to uncover novel targets for intervention strategies.