Clusterin as a therapeutic agent: Bridging the gap in brain and eye research.

Clusterin (CLU) is a multifunctional secreted glycoprotein that is widely expressed in human tissues and body fluids. It plays critical roles in maintaining tissue homeostasis, regulating inflammation, modulating immune responses, and promoting cellular survival in both the brain and the eye. The CLU gene undergoes alternative splicing, yielding protein isoforms with distinct, and sometimes opposing, functions within a single disease condition. While secreted CLU (sCLU) is generally associated with cytoprotection, regulation of complement activation, protein chaperoning, and resolution of inflammation, the nuclear CLU (nCLU) isoform have been implicated in cell stress responses, apoptosis, and disease progression. Understanding these isoform-specific functions is essential for interpreting the diverse and sometimes contradictory roles of CLU across disease states. In this review, we discuss endogenous CLU expression, alternative splicing, and the resulting functions of its different isoforms. In addition to its inherent physiological role, we review recent research on exogenous CLU administration in the eye and brain. We identify knowledge gaps that need to be addressed before CLU is developed as a therapeutic agent. To help with the identification of future drug targets, we also summarize common CLU mechanisms in the brain and eye. By combining and contrasting knowledge from these two interconnected organs, we identify convergent CLU-regulated pathways and therapeutic opportunities, providing a comprehensive guide to future mechanistic studies, biomarker development, and CLU-based drug discovery. Therefore, the summaries in this review make it a highly relevant reference for CLU translational research and drug discovery across multiple brain and eye disorders.