The fibrocystin C-terminal domain inhibits Src/STAT3 signal induced cystogenesis of kidney epithelial cells.

Modulation of Cyst Growth in Autosomal Dominant Polycystic Kidney Disease: Mechanistic Insights and Therapeutic Opportunities.

A model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs is synthesized, which support a model in which cyst growth arises from mutually reinforcing signaling, metabolic, and transcriptional programs.

Ubiquitin-Specific Protease 11 Promotes Uric Acid-Induced Renal Tubular Epithelial Cell Apoptosis via Deubiquitinating P53 and Enhancing Mitochondrial Outer Membrane Permeabilization

The results underscore the pivotal role of USP11 in TEC apoptosis during CKD progression and suggest that targeting USP11 represents a potential therapeutic approach for CKD patients.

Ubiquitin-specific protease 11 promotes tubular cell senescence via inhibiting p53 ubiquitin degradation during renal fibrosis.

Emerging evidence has established that renal tubular epithelial cell (TEC) senescence is an essential driver of renal fibrosis, while the activation of p53/p21 pathway plays a key role in initiating TEC senescence. However, the upstream regulatory mechanisms of p53/p21 pathway activation remain unclear, hindering the development of targeted anti-fibrotic therapies for chronic kidney disease (CKD). This study aimed to reveal the upstream regulator of the p53/p21 pathway and investigate its role in renal fibrosis. Here, we report that unilateral ureteral ligation (UUO) and folic acid (FA)-induced fibrotic mouse kidneys exhibited a marked senescent phenotype and activated p53/p21 pathway, accompanied by significant upregulation of ubiquitin-specific protease 11 (USP11). These changes were further verified in angiotensin II (Ang II)-stimulated HK-2 cells. Both Usp11 knockout and pharmacological inhibition with mitoxantrone (MTX) significantly alleviated UUO-induced p53/p21 pathway activation, tubular senescence and renal fibrosis. Mechanistically, USP11 directly interacted with p53 and protected it from ubiquitin-dependent degradation, thereby promoting tubular cell senescence and fibrosis. Furthermore, we identified Krüppel-like factor 4 (KLF4) as the upstream transcription factor that directly bound to the USP11 promoter and enhanced its transcription under pathological conditions. Our findings demonstrate that the KLF4-USP11-p53 axis drives tubular senescence and renal fibrosis, representing a highly promising therapeutic target for CKD.

PDE4D-CXCL13 axis in gland epithelial cells promotes B cell infiltration in primary Sjögren's syndrome.

Cdc42 small GTPase is a novel regulator of the fibrogenic activation of human intestinal myofibroblasts

Blocking the Phase Separation of hnRNP L Attenuates Pulmonary Fibrogenesis by Inhibiting Fibroblast-to-myofibroblast Differentiation.

INTRODUCTION Pulmonary fibrosis is an interstitial lung disease characterized by diverse etiologies and unknown mechanisms. Phase separation has been implicated in the development of numerous diseases, but its role in the pathogenesis of pulmonary fibrogenesis remains unclear. In this study, we explored whether heterogeneous nuclear ribonucleoprotein L (hnRNP L) can form phase-separation condensates that contribute to the progression of pulmonary fibrosis. METHODS Pulmonary fibrosis was modeled in vitro using TGF-β1-treated fibroblasts and in vivo by intratracheal bleomycin administration in mice. Phase-separation formation was evaluated by droplet formation and fluorescence recovery after photobleaching experiments. Adeno-associated virus vectors overexpressing full-length hnRNP L or hnRNP L-Δ26-111 & 274-374 (truncation of amino acid fragments 26-111 and 274-374) were constructed and delivered into murine lungs using a Penn-Century MicroSprayer device. Micro-computed tomography imaging, forced vital capacity tests, hematoxylin and eosin staining, and Masson's trichrome staining were performed to assess the anti-fibrotic effect of disrupting hnRNP L phase separation. RNA-seq was employed to explore the underlying molecular targets of hnRNP L. RESULTS In vivo and in vitro results revealed that the role of hnRNP L in promoting fibroblast differentiation depended on its phase separation, and the amino acid fragments 26-111 and 274-374 were essential to this process. Phenotypic, physiological, and histological analyses demonstrated that hnRNP L overexpression accelerated the development of pulmonary fibrogenesis. In contrast, truncated hnRNP L-Δ26-111 and 274-374 improved lung tissue structure and function and reduced collagen deposition by blocking hnRNP L phase separation. RNA-seq results showed that a total of 1,155 dysregulated genes (FDR < 0.05, |logFC| > 1) were detected after silencing hnRNP L using small interfering RNA (siRNA) in TGF-β1-treated MRC-5 cells. Most differentially expressed genes were related to lung fibrosis, including TGFBR1, CXCL8, WWTR1, FAP, VIM, α-SMA, and collagen. The RNA levels of these genes were evidently regulated by silencing or overexpressing hnRNP L. Notably, we observed that hnRNP L phase separation promoted histone modifications such as H3K27ac, H4K8la, H4K12la, and H4K16la, which are associated with active chromatin. DISCUSSION Our findings reveal that TGF-β1-enhanced phase separation of the chromatin-associated RBP hnRNP L promotes gene transcription and facilitates profibrotic phenotypes in lung myofibroblasts, suggesting a phase-separation-based therapeutic strategy. CONCLUSION Blocking hnRNP L phase separation inhibited fibroblast-to-myofibroblast differentiation, attenuating pulmonary fibrogenesis. This study reveals a novel regulatory mechanism by which phase separation contributes to the development of pulmonary fibrosis.