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FAM40A Deficiency Activates the Hippo Pathway to Promote Podocyte Apoptosis and Contribute to FSGS

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Article Type: Review Article Published: 2025-12-16 Volume/Issue: 6 / 12 Pages: 1911-1928

FAM40A Deficiency Activates the Hippo Pathway to Promote Podocyte Apoptosis and Contribute to FSGS

Chen Z and Guo Z
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Pathology Nephrology
FAM40A Deficiency Activates the Hippo Pathway to Promote Podocyte Apoptosis and Contribute to FSGS
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Abstract

<p><b>Background:</b> Focal Segmental Glomerulosclerosis (FSGS), a major cause of end-stage renal disease, is characterized by podocyte loss via apoptosis and cytoskeletal disruption. Although dysregulation of the Hippo-YAP pathway is implicated in podocyte injury, upstream regulators of this pathway in FSGS pathogenesis remain elusive.<br><b>Methods: </b>To determine whether FAM40A deficiency precipitates FSGS, we generated heterozygous FAM40A+/− mice by CRISPR/Cas9-mediated deletion of exons 3-8 (Δex3-8 allele). At specified time points, kidneys were collected for histological examination (PAS, TEM), immunofluorescence, and Western blotting to quantify podocyte apoptosis and Hippo pathway activation. Finally, FAM40A+/− mice were randomly assigned to receive treatment with the MST1/2 inhibitor XMU-MP-1 (1 mg/kg/day) via intraperitoneal injection or vehicle treatment for 10 days. Endpoints included urinary Albumin-to-Creatinine Ratio (ACR), renal histology, podocyte density, and podocyte apoptosis markers.<br><b>Results: </b>We identified FAM40A as a novel negative regulator of the Hippo pathway in podocytes. FAM40A directly suppressed the kinase activity of Mst1/2, thereby preventing phosphorylation and inactivation of the downstream effector YAP. FAM40A deficiency triggered Mst1/2 activation, leading to YAP phosphorylation, nuclear exclusion, and transcriptional repression. This cascade resulted in podocyte apoptosis and exacerbated FSGS phenotypes In vivo.<br><b>Conclusion: </b>Our study defines the FAM40A-Mst1/2-YAP axis as a critical signalling pathway governing podocyte survival. Loss of FAM40A activates Hippo signalling to promote podocyte apoptosis and FSGS progression. While short-term MST1/2 inhibition ameliorates disease features in mice, further evaluation of safety and feasibility is required. These findings highlight FAM40A as a potential therapeutic target for FSGS.<br></p>

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