Mechanism of Nuclear Protein PCNP in Scar Processes and Applications for Scar
Abstract
PEST-containing nuclear protein (PCNP), a short-lived nuclear protein with dual PEST domains, is closely involved in scar formation and repair by regulating fibroblast function, fibrotic signaling, inflammation, and collagen metabolism. It acts as a key negative regulator of pathological scar hyperplasia, and its targeted modulation provides a novel strategy for scar prevention and treatment. This paper systematically elaborates the molecular mechanism of PCNP in scar processes and its translational applications in scar management.
1. Mechanism of PCNP in Scar Formation and Repair
Scar formation is a dynamic process involving inflammation, fibroblast activation, collagen deposition, and tissue remodeling. PCNP exerts its regulatory effects through multiple molecular pathways, mainly inhibiting pathological scar hyperplasia by suppressing excessive proliferation and fibrotic activation of scar-related cells.
1.1 Regulation of Fibroblast Proliferation and Apoptosis via the p53-p21 Axis
PCNP directly interacts with the DNA-binding domain of p53, enhancing the transcriptional activity of p53 and promoting the expression of its downstream target gene p21. p21 inhibits cyclin-dependent kinases (CDKs), blocking the G2/M phase transition of scar-derived fibroblasts and reducing excessive cell proliferation. Meanwhile, PCNP activates the p53-mediated apoptotic pathway, inducing apoptosis of hyperactive myofibroblasts, thereby reducing the number of collagen-secreting cells and inhibiting scar hyperplasia.
1.2 Inhibition of Fibrotic Signaling Pathways
Wnt/β-catenin pathway: PCNP binds to the ARM domain of β-catenin, promoting its ubiquitination and degradation, and blocking its nuclear translocation. This inhibits the transcription of fibrotic target genes (Collagen I/III, α-SMA, c-Myc), thereby reducing myofibroblast transdifferentiation and collagen over-deposition.
TGF-β/Smad pathway: PCNP downregulates the expression and nuclear accumulation of Smad2/3, the key transcription factors of the TGF-β1 pathway, weakening the pro-fibrotic signal transduction and alleviating scar fibrosis.
1.3 Attenuation of Inflammatory Response
PCNP inhibits the activation and nuclear translocation of NF-κB, a core inflammatory nuclear protein, reducing the expression of pro-inflammatory cytokines (IL-6, TNF-α) in scar tissue. By mitigating excessive inflammatory infiltration, PCNP interrupts the "inflammation-fibrosis" positive feedback loop, preventing the progression of acute inflammation to chronic fibrosis and pathological scar formation.
1.4 Regulation of Collagen Metabolism Balance
PCNP upregulates the expression of matrix metalloproteinases (MMPs, such as MMP-1, MMP-3) and downregulates tissue inhibitors of metalloproteinases (TIMPs), restoring the balance between collagen synthesis and degradation in scar tissue. This promotes the degradation of excessive collagen, accelerates scar remodeling, and reduces scar density and hardness.
1.5 Modulation of Cell Cycle and Extracellular Matrix Remodeling
As a short-lived nuclear protein, PCNP exhibits cell cycle-dependent expression (high in G2/M phase), coordinating with histone synthesis to regulate the proliferation rhythm of scar fibroblasts. Its PEST domain mediates rapid protein degradation, dynamically adjusting the intensity of pro-fibrotic signal inhibition and maintaining the stability of tissue repair.
2. Applications of PCNP in Scar Management
Based on the anti-fibrotic mechanism of PCNP, its applications in scar prevention, diagnosis, and treatment have broad prospects, providing new targets and strategies for clinical scar management.
2.1 As a Diagnostic and Prognostic Biomarker
The expression level of PCNP in scar tissue and peripheral blood is negatively correlated with the degree of scar hyperplasia: low PCNP expression is associated with severe hypertrophic scars and keloids, while high PCNP expression indicates mild scarring and good repair.
Detecting PCNP expression by immunohistochemistry, qPCR, or serum ELISA can predict the risk of pathological scar formation after trauma/surgery and evaluate the efficacy of scar treatment, realizing early warning and dynamic monitoring of scars.
2.2 Targeted Therapy for Pathological Scars
Small molecule targeted drugs: Screen small molecule compounds that upregulate PCNP expression or enhance its stability (e.g., inhibitors targeting PCNP-NIRF interaction) to restore PCNP function in scar tissue, inhibiting fibroblast activation and collagen deposition.
Gene therapy: Deliver PCNP overexpression vectors (adenovirus, lentivirus) to scar tissue via local injection or biomaterial carriers, increasing PCNP levels and reversing the fibrotic phenotype of scar cells.
CRISPR gene editing: Optimize the PEST domain or phosphorylation sites of PCNP to enhance its anti-fibrotic activity, providing a permanent therapeutic strategy for refractory keloids.
2.3 Combined with Traditional Scar Treatments
PCNP-targeted therapy can be combined with conventional treatments (hormone injection, laser, silicone gel) to synergistically improve efficacy:
PCNP agonists combined with laser therapy reduce scar inflammation and collagen regeneration;
PCNP gene therapy combined with local hormone injection reduces the side effects of hormones while enhancing the anti-scar effect.
2.4 Application in Regenerative Medicine and Biomaterials
Modify tissue-engineered skin scaffolds with PCNP recombinant protein to promote normal skin regeneration and reduce scar formation during wound repair;
Combine PCNP with stem cell therapy to regulate the paracrine function of stem cells, enhance their anti-fibrotic effect, and optimize scar repair outcomes.
3. Conclusion
PCNP is a key negative regulator of pathological scar formation, exerting anti-fibrotic effects through multiple pathways such as regulating fibroblast proliferation/apoptosis, inhibiting fibrotic signaling, and attenuating inflammation. It has important application value as a scar biomarker and therapeutic target. In-depth research on the mechanism of PCNP in scar processes will promote the development of precise and individualized scar treatment strategies, providing new solutions for clinical prevention and treatment of hypertrophic scars and keloids.
