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SM Journal of Nephrology and Kidney Diseases

Renal Fibrosis: A Peripheral Prionopathy?

[ ISSN : 2576-5450 ]

INTRODUCTION Figure 1 Figure 2 REFERENCE
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Received: 23-Aug-2025

Accepted: 24-Aug-2025

Published: 29-Aug-2025

Review Article | Volume 6 - Issue 1 | Article DOI : https://dx.doi.org/10.36876/smjnkd.1031

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Wen-Quan Zou*, Yirong Yang

Institute of Neurology, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China

Corresponding Author:

Wen-Quan Zou, Institute of Neurology, Jiangxi
Academy of Clinical Medical Sciences, The First Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang, Jiangxi Province
330006, China.

INTRODUCTION

Renal fibrosis, the common pathological endpoint of Chronic Kidney Disease (CKD), represents a global health challenge due to its high prevalence and limited therapeutic options [1]. Despite its clinical significance, the molecular mechanisms driving this process remain poorly understood. In a landmark cover study published in Science Translational Medicine, Long et al. identified a novel mechanism by which cellular prion protein (PrPC) drives renal fibrosis through Liquid-Liquid Phase Separation (LLPS). Their work reveals that PrPC forms pathologically active biomolecular condensates, which aberrantly activate the TBK1–IRF3 signaling axis, establishing a critical link between phase separation and fibrotic disease progression [2]. Meanwhile, the team identified Amlexanox—a clinical-stage inhibitor of TBK1-IRF3—as a promising therapeutic candidate (Figure 1). This work not only establishes PrPC-LLPS as a key regulator of fibrosis but also proposes a translational strategy: targeting the PrPC-TBK1-IRF3 axis could address current treatment gaps. The repurposing potential of Amlexanox may accelerate drug development for CKD.

PrPC, a glycosylphosphatidylinositol (GPI)-anchored cell-surface glycoprotein, is best known for its role in prion diseases, fatal neurodegenerative disorders caused by its misfolded isoform, PrPSc [3]. While the physiological functions of PrPC remain incompletely defined, emerging evidence suggests a protective role in ischemia-reperfusion injury (Figure 2). For example, wild-type mice exhibit significantly smaller infarct sizes in ischemic tissues compared to PrP gene (PRNP) knockout mice, attributed to PrPC-mediated activation of ERK1/2 signaling and antioxidant responses (e.g., heme oxygenase-1 induction) [4-6]. However, it is noteworthy that its misfolded isoform PrPSc, as a nucleic acid-free infectious pathogen, has been identified as the pathogenic core of classical cerebral prion diseases, with its pathological manifestations currently observed exclusively in the central nervous system (Figure 2) [7]. The current findings from Long et al have for the first time revealed a mechanism by which the PrPC condensate induces pathological alterations in peripheral organs through a possible non-PrPSc form (Figure 2).

This discovery raises three critical questions: 1) Subcellular localization of PrPC condensates: In classical prion diseases, PrPC–PrPSc conversion occurs mainly at cellular membranes [8]. However, the precise site (plasma membrane vs. cytoplasm) of PrPC condensate formation in renal tubules remains unresolved. 2) Transmissibility of fibrosis-associated PrPC aggregates: PrPSc aggregates in prion diseases exhibit infectivity and seeding activity in brain, cerebrospinal fluid, and skin [3,9]. Whether renal PrPC aggregates in the kidney possess similar transmissible properties requires rigorous interdisciplinary validation. 3) Generalizability to other fibrotic disorders: It remains unclear whether PrPC contributes to fibrosis in organs such as the liver or lungs. Addressing this could redefine fibrotic pathogenesis and introduce the concept of “peripheral-type prionopathy.” By bridging prion biology and fibrotic disease mechanisms, this study opens new frontiers for understanding protein misfolding disorders and developing therapies for CKD and beyond.

 

Figure 1

Figure 1: Mechanistic role of PrPC condensates in driving renal fibrosis via the TBK1-IRF3 signaling pathway [2]. +: Increasing effects; -: Decreasing effects.

Figure 2

Figure 2: Schematic overview of PrPC, PrPSc, and PrPC condensates: dual physiological and pathophysiological roles across central and peripheral organ systems. The solid blue triangle with an enclosed 'P' denotes phosphorylation of the associated molecule

REFERENCE

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  2. Long T, Lu Y, Ma Y, Song Y, Yi X, et al. (2025). Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis. Sci Transl Med. 17: 794.

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  6. Zanetti F, Carpi A, Menabò R, Giorgio M, Schulz R, et al. (2014). The cellular prion protein counteracts cardiac oxidative stress. Cardiovasc Res. 104: 93-102.

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  8. Poggiolini I, Saverioni D, Parchi P. (2013). Prion protein misfolding, strains, and neurotoxicity: an update from studies on Mammalian prions. Int J Cell Biol. 2013: 910314.

  9. Orrú CD, Yuan J, Appleby BS, Li B, Li Y, et al. (2017). Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med. 9: 417.

Citation

Zou W, Yang Y (2025) Renal Fibrosis: A Peripheral Prionopathy?.J Nephrol Kidney Dis 6(1): 2.