ROCK signaling at the interface of fibrosis and neurodegeneration: mechanisms and therapeutic potential

Rho-associated coiled-coil containing protein kinases 1 and 2 (ROCK1 and ROCK2) regulate cytoskeletal dynamics, actomyosin contractility, extracellular matrix remodeling, and responses to mechanical stress. In the eye and central nervous system (CNS), these functions intersect with fibrocontractile scarring, neuronal dysfunction, impaired regeneration, and neuroinflammation. This review examines ROCK signaling at the interface of ocular fibrosis and neurodegeneration, emphasizing the retina as a setting in which neural injury and pathological remodeling can coexist. We outline the physiological and pathological consequences of ROCK-mediated mechanotransduction, using peripheral fibrosis only as brief comparative context, and examine its relationship with MRTF/SRF and YAP/TAZ transcriptional modules. We then assess evidence from ocular fibrotic disease, axonal regeneration, synaptic plasticity, microglial activation, and CNS injury-associated scarring, distinguishing direct ROCK-dependent mechanisms from extrapolation across tissues. ROCK1 and ROCK2 display overlapping functions with context-dependent specialization, but current evidence does not support a universal division of labor between the isoforms. Single-cell, spatial, and multi-omics approaches offer opportunities to identify disease-relevant cell populations, although transcript abundance alone cannot establish kinase activity or therapeutic dependence. Finally, we consider ocular and neural therapeutic development, including isoform-informed targeting, local delivery, and mechanism-aligned combinations. The central challenge is to suppress persistent pathological remodeling while preserving physiological repair and beneficial neural or glial responses. Resolving the cellular, spatial, and temporal requirements for ROCK signaling will be essential for testing whether antifibrotic and neuroprotective effects can be achieved together.