Cell Immunol. 2025 Nov 21;420-421:105053. doi: 10.1016/j.cellimm.2025.105053. Online ahead of print.
ABSTRACT
Obstructive nephropathy is characterized by progressive renal inflammation and tubular injury, in which the NLRP3 inflammasome plays a pivotal role. However, the contribution of cytoskeletal dynamics to inflammasome activation remains poorly understood. In this study, we investigated whether stabilizing the actin cytoskeleton using Bis-T-23, a filamentous actin (F-actin) stabilizer, could alleviate renal injury by suppressing NLRP3 signaling. In a unilateral ureteral obstruction (UUO) mouse model, Bis-T-23 treatment significantly reduced tubular dilation, interstitial fibrosis, and immune cell infiltration. Transcriptomic profiling revealed marked downregulation of inflammation-related pathways, including TNF, IL-17, and NOD-like receptor signaling. At the molecular level, Bis-T-23 inhibited NLRP3 inflammasome activation, as evidenced by decreased levels of NLRP3, cleaved caspase-1, IL-1β, and IL-18 in both renal tissue and tubular epithelial cells. In vitro, TNFα/TGFβ1 co-stimulation induced a pro-fibrotic and pro-inflammatory phenotype in tubular cells, characterized by ZO-1 disruption, α-SMA upregulation, and enhanced NLRP3 expression, all of which were reversed by Bis-T-23. Furthermore, Bis-T-23 impaired ASC speck formation and disrupted NLRP3-ASC interactions, suggesting a direct blockade of inflammasome assembly. These findings identify cytoskeletal stabilization as a novel upstream mechanism for NLRP3 regulation and highlight Bis-T-23 as a potential therapeutic candidate for mitigating tubular inflammation in obstructive kidney disease.
PMID:41285084 | DOI:10.1016/j.cellimm.2025.105053