Progranulin (PGRN), also known as granulin–epithelin precursor (GEP), proepithelin, acrogranin, and GP88/PC-cell derived growth factor, is a 593-amino-acid glycoprotein [1]. PGRN contains seven-and-a-half repeats of a cysteine-rich motif in the order, P–G–F–B–A–C–D–E, where A–G are full repeats and P is the half-motif [2]. PGRN is highly expressed in epithelial cells, neurons and macrophages, and is likewise expressed in a broad range of other tissues and cell-types including skeletal muscle, cartilage, adipose tissue, hematopoietic cells, and some immune cells like T cells and dendritic cells [3].

PGRN initially was found as a growth factor that promotes cell proliferation [4]. The discovery of PGRN’s neurotropic function was simultaneously reported by two individual groups who have shown that a PGRN mutation leads to frontotemporal lobar degeneration (FTLD)[5], [6]. Following this study, other groups have also found that PGRN imbalance are associated with Alzheimer's disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), motor neuron disease, multiple sclerosis, and Creutzfeldt-Jakob disease [3]. PGRN has been identified as a crucial molecule in numerous inflammation and developmental disease processes, including autoimmune diseases and musculoskeletal disorders. Additionally, the identification of PGRN as a co-chaperone molecule and an essential lysosomal protein also provides a mechanistic explanation for the association between PGRN insufficiency and a wide range of diseases affecting the central nervous system, peripheral organs, and visceral organs [3]. These disorders are collectively referred to as Progranulinopathy, encompassing the broad spectrum of conditions influenced by PGRN imbalance. Recent Bateman’s [7] and Simon's [8] reviews nicely center around the role of PGRN in lysosomal functions and its potential implications in the treatment of neurodegenerative diseases. Previously, our team also summarizes available knowledge of PGRN in various kinds of diseases, including common neurological diseases, inflammatory autoimmune diseases, and rare lysosomal storage diseases [3], [9], [10], [11], [12], [13], [14], [15]. Understanding the underlying mechanisms of progranulinopathy and the specific pathways and interactions involved in PGRN-related diseases is crucial for the development of targeted therapies and diagnostic approaches. Thus, in this updated prospective review paper, we will discuss how PGRN fits in the pathogenesis puzzle in those diseases, and provide insights into novel therapeutic potential of PGRN or PGRN-derived molecules to treat progranulinopathy. Furthermore, this review will provide updates on recently discovered novel PGRN-associated proteins and explore their potential functions in mediating various PGRN actions.