Work

NF2 Inhibits CMPK2-Driven NLRP3 Inflammasome Activation to Alleviate Podocyte Injury in FSGS

Year: 2026

Type: article

Abstract: Background & Aims: Therapeutic strategies directly targeting podocyte injury in focal segmental glomerulosclerosis (FSGS) are limited. Although NF2 is known to regulate cytoskeletal dynamics and cellular homeostasis, its role in podocyte inflammatory injury and downstream mechanisms remains unclear. This study investigated the function of NF2 and its regulatory relationship with CMPK2 in FSGS. Methods: NF2 expression was assessed in kidney tissues from FSGS patients and experimental models. In vivo and in vitro models were used to evaluate the effects of NF2 modulation on podocyte function. Gain- and loss-of-function approaches examined NF2-CMPK2 interactions and downstream inflammatory signaling pathways. Results: NF2 was predominantly expressed in podocytes and significantly downregulated in kidney tissues from FSGS patients and experimental models. NF2 knockdown in human podocytes upregulated CMPK2, activating the NLRP3 inflammasome and promoting IL-1β release, leading to enhanced inflammatory injury. Conversely, NF2 overexpression suppressed CMPK2, inhibited NLRP3 inflammasome activation, reduced IL-1β production, and alleviated podocyte injury. Conclusion: Our findings indicate that NF2 confers protection against podocyte inflammatory injury, likely via modulation of the CMPK2-NLRP3 inflammasome signaling, pointing to a potential therapeutic target for FSGS.

Source: Journal of Inflammation Research

DOI: 10.2147/jir.s615100