Voclosporin Preserves Mitochondrial Function Compared With Cyclosporine A in Perfused Human Proximal Tubule Microphysiological Systems

In 3D MPS, CsA increased aggregate biomarker deviations, whereas VOC responses remained near vehicle (CsA was ~1.8-fold higher than VOC; two-way ANOVA drug main effect, F = 71.99, p < 0.0001). Confocal tomography showed CsA-associated mitochondrial fragmentation and a ~ 40% reduction in ΔΨm, whereas VOC preserved network architecture and ΔΨm (p < 0.0001). RNA-seq identified 1188 CsA-specific and 185 VOC-specific differentially expressed genes, with 304 shared.

Pathway analysis indicated CsA enrichment of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, p21-associated G2/M checkpoint arrest, and ferroptosis-prone signatures, while VOC mainly induced ER chaperone and ER-associated degradation gene programs without activating canonical UPR sensors and showed limited cell-cycle suppression. A physiologically relevant 3D kidney MPS revealed sublethal tubular stress from CsA that is masked in 2D culture, including mitochondrial depolarization, proteostatic stress, and ferroptosis priming.

A matched exposure, VOC preserved mitochondrial and proteostasis and elicited a narrower, adaptive ER quality control response. These data support VOC as a nephron-sparing immunosuppressant and 3D MPS as a mechanism-based platform for evaluating renal safety of drugs and nominating early sub-lethal tubular injury biomarkers.