ACBD5 as a Master Tether of Peroxisomes: Integrating Organelle Contact Sites, Lipid Sensing, and Cellular Homeostasis

Acyl-CoA-binding domain-containing proteins (ACBDs) constitute a large and diverse multigene family involved in cellular lipid metabolism. Among them, the tail-anchored peroxisomal membrane protein ACBD5 has emerged as a key component of peroxisome–endoplasmic reticulum (ER) contact sites through its interaction with VAMP-associated proteins (VAPs). More recently, ACBD5 has also been implicated in peroxisome–mitochondria tethering under conditions of oxidative stress. Although initially characterized as a lipid-binding peroxisomal membrane protein, ACBD5 is increasingly recognized as a central mediator of inter-organelle cooperation. Here, we propose an expanded view of ACBD5 function, suggesting that it acts as a peroxisomal “master tether” that integrates intracellular organisation with metabolic and homeostatic regulation. By linking lipid sensing and metabolism to the formation and regulation of membrane contact sites, ACBD5 may serve as a key organizer of peroxisomal interactions within the cellular organelle network. We discuss the role of peroxisomes as interconnected hubs of cellular cooperation, examine the functions of ACBD5 at peroxisome–ER contact sites and beyond, highlight its relevance to human disease, and present a conceptual framework for understanding ACBD5 as a peroxisomal master tether.