4-Phenylbutyrate mitigates renal pathology linked to ER stress related pathways in C57BL/6J mice with hindlimb unloading.

4-Phenylbutyrate (4-PBA), a chemical chaperone known to reduce endoplasmic reticulum (ER) stress—a key contributor to kidney injury and fibrosis—has shown therapeutic potential in various disease models. However, the impact of hindlimb unloading (HU) on renal ER stress and its transcriptomic landscape remains poorly characterized. To our knowledge, this study provides the first comprehensive transcriptomic profiling of HU-induced renal alterations and their modulation by 4-PBA in C57BL/6J mice. To evaluate the protective effects of 4-PBA against HU-induced renal injury, mice were divided into three groups: ground-based controls (GC), HU mice receiving vehicle treatment (HU), and HU mice treated with 4-PBA. Renal histological and molecular alterations were assessed, and RNA sequencing was performed using the Illumina platform to characterize ER stress-related gene expression changes. HU induced significant ER stress-associated protein dysregulation and renal pathological alterations, which were partially attenuated by 4-PBA treatment. Gene Ontology enrichment analysis confirmed elevated ER stress signaling in HU kidneys and its reduction following 4-PBA administration. KEGG and Reactome pathway analyses further demonstrated modulation of multiple ER stress-associated and cytoprotective pathways with 4-PBA treatment. These findings provide transcriptomic-level evidence that 4-PBA mitigates HU-induced renal stress responses and support its potential as a therapeutic strategy for renal dysfunction associated with microgravity, prolonged immobilization, or sedentary conditions.