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.

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

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).

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.

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.

Zou WQ, Yang Y (2025) Renal Fibrosis: A Peripheral Prionopathy?. Ann Neurodegener Dis 9(1): 1041.

1. Abbad L, Esteve E, Chatziantoniou C. Advances and challenges in kidney fibrosis therapeutics. Nat Rev Nephrol. 2025; 21: 314-329.
2. Long T, Lu Y, Ma Y, Song Y, Yi X, Chen X, et al. Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis. Sci Transl Med. 2025; 17: eadj9095.
3. Prusiner SB. Prions. Proc Natl Acad Sci USA. 1998; 95: 13363-13383.
4. Spudich A, Frigg R, Kilic E, Kilic U, Oesch B, Raeber A, et al. Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1. Neurobiol Dis. 2005; 20: 442-449.
5. Zhang B, Cowden D, Zhang F, Yuan J, Siedlak S, Abouelsaad M, et al. Prion Protein Protects against Renal Ischemia/Reperfusion Injury. PLoS One. 2015; 10: e0136923.
6. Zanetti F, Carpi A, Menabò R, Giorgio M, Schulz R, Valen G, et al. The cellular prion protein counteracts cardiac oxidative stress. Cardiovasc Res. 2014; 104: 93-102.
7. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull. 2003; 66: 213- 239.
8. Poggiolini I, Saverioni D, Parchi P. Prion protein misfolding, strains, and neurotoxicity: an update from studies on Mammalian prions. Int J Cell Biol. 2013; 2013: 910314.
9. Orrú CD, Yuan J, Appleby BS, Li B, Li Y, Winner D, et al. Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med. 2017; 9: 7785.