Abstract: Homeostasis of tissue metabolism is fundamental to maintaining tissue structure and function, and metabolic dysregulation is closely associated with the pathogenesis and progression of various diseases. Consequently, modulating tissue metabolic homeostasis has emerged as a critical therapeutic target for disease intervention. Leveraging their unique interfacial lubrication and tunable physicochemical properties, lubricating molecular materials not only mitigate mechanical damage but also actively intervene in tissue metabolic networks through multidimensional regulatory strategies. In this review, we highlight diverse lubricating molecular materials, provide an in-depth analysis of their multifunctional modes of regulating tissue metabolism, and discuss their applications in disease contexts. Finally, we outline the current challenges and future prospects of this rapidly evolving field.