====== Pirin ====== {{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1nMk785v90DULMn7CQvkjnGOQoxlvDUASakpD-m2p5yJyzqEdB/?limit=15&utm_campaign=pubmed-2&fc=20250630191311}} ---- ---- ====== Pirin ====== **Definition:** *Pirin* is a highly conserved nuclear protein belonging to the cupin superfamily. It functions as a **transcriptional co-regulator**, interacting with key factors such as **NF-κB**, and is implicated in **oxidative stress responses**, **inflammation**, and **cancer progression**. ===== Molecular Characteristics ===== * **Gene:** *PIR* (located on chromosome 1q21.3 in humans). * **Structure:** Contains a cupin-like β-barrel domain capable of binding metal ions (e.g., iron, zinc). * **Localization:** Mainly nuclear, but cytoplasmic presence observed in some cancers. ===== Functional Roles ===== ^ Function ^ Description ^ | **Redox sensor** | Pirin activity is modulated by cellular redox state, especially Fe²⁺/Fe³⁺ ratio. | | **NF-κB co-regulator** | Enhances or modulates NF-κB–dependent gene transcription. | | **Cell migration & EMT** | Associated with epithelial–mesenchymal transition (EMT) and metastasis. | | **Pro-inflammatory signaling** | Upregulated in response to inflammatory stimuli. | ===== Involvement in Cancer ===== * **Oncogenic potential:** Pirin is overexpressed in several cancers including **melanoma**, **lung cancer**, **breast cancer**, and **gliomas**. * **Promotes EMT and metastasis:** Through modulation of NF-κB and other pathways. * **Possible biomarker:** Elevated PIR expression correlates with poor prognosis in multiple tumor types. * **Potential therapeutic target:** Inhibition of pirin-NF-κB interaction is under investigation. ===== Relation to Inflammation ===== * Pirin is induced by oxidative stress and inflammatory cytokines (e.g., TNF-α, IL-1β). * Acts as a **redox-sensitive transcriptional regulator**—key in linking inflammation to tumorigenesis. ===== Research Highlights ===== * Pirin modulates **IL-8** and **matrix metalloproteinase (MMP)** expression in cancer cells. * Studies show **iron-bound pirin (holo-pirin)** promotes pro-inflammatory transcriptional programs more than its iron-free form. * Possible link to **neuroinflammation** via glial activation and redox imbalance. ===== Clinical and Research Implications ===== * **Cancer biology:** Pirin may serve as a prognostic biomarker and therapeutic target in aggressive cancers. * **Redox-inflammation axis:** Represents a molecular hub for oxidative stress and chronic inflammation. * **Neurology:** Under investigation for its role in neuroinflammation and neurodegeneration. ===== References ===== * Wendler WM, et al. (2006). Pirin, a novel nuclear protein, interacts with NF-κB p65 and modulates its transcriptional activity. *J Biol Chem*. * Liu Y, et al. (2019). Pirin regulates epithelial–mesenchymal transition in lung cancer via NF-κB pathway. *Oncol Rep*. * De Simone G, et al. (2013). Pirin as a potential target in cancer therapy. *FEBS Lett*. ---- ===== Experimental studies ===== In a **[[Experimental study]]** using [[in vitro]] [[cell line]]s and [[in vivo]] [[mouse]] [[model]]s, supplemented with [[transcriptomics]], [[western blotting]], [[qRT-PCR]], [[immunofluorescence]], and [[immunohistochemistry]]. **Ma et al.** from the Xiamen University, [[Xiamen]], China. published in the *[[Gut Journal]]*, online ahead of print: **June 27, 2025**. to investigate **Pirin (PIR)** as a redox-sensitive transcriptional regulator and pro-inflammatory factor in [[hepatocellular carcinoma]] (HCC) pathogenesis ((Ma H, Cao T, Zhang F, Sun D, Chen L, Lin Y, Lai S, Jiang B, Zhou Y, You J, Liu X, Wang Y, Lin F, Liu Y, Wang J, He W, Li Q. Nuclear [[Pirin]] promotes HCC by acting as a key [[inflammation]]-facilitating factor. Gut. 2025 Jun 27:gutjnl-2024-334087. doi: 10.1136/gutjnl-2024-334087. Epub ahead of print. PMID: 40579121.)). ===== Key Results ===== 1. PIR undergoes **redox-mediated nuclear translocation**, enhancing inflammatory transcription via [[RELA]]. 2. This creates a **positive feedback loop** that increases proinflammatory [[cytokine]]s and promotes HCC progression. 3. PIR inhibition (genetic/pharmacological) or treatment with **[[N-acetyl cysteine]]** attenuates [[tumor growth]] and inflammation in mouse models. 4. Liver parenchymal cells demonstrate autocrine cytokine production under PIR influence, directly contributing to malignancy. ===== Critical Review ===== - **Strengths**: - Mechanistically rich; integrates redox biology, transcriptional regulation, and tumor immunopathology. - Robust experimental design across molecular, cellular, and organismal levels. - Data support PIR as a **central inflammatory amplifier** with translational potential. - **Limitations**: - The study remains **preclinical** — lacking validation in human tissue cohorts or prospective clinical samples. - While inflammation is implicated, **direct links to immune cell behavior or microenvironmental shifts** remain underexplored. - Therapeutic interventions like NAC, although promising, need careful **pharmacokinetic validation** for clinical extrapolation. - The oncogenic specificity of PIR needs contrast with other tumor models—i.e., is this HCC-specific or broadly pro-tumorigenic? ===== Final Verdict ===== - **Score**: 8/10 — a conceptually innovative, well-executed mechanistic study with significant translational implications, pending clinical correlation. ===== Takeaway for Neurosurgeons ===== While not directly neurosurgical, this study reinforces the **broader principle** that [[redox]]-sensitive [[transcriptional regulator]]s (like PIR) may be **[[pro-inflammatory oncogenic driver]]s**—a paradigm potentially relevant in [[glioma]]s or other CNS tumors influenced by [[inflammation]]. ===== Bottom Line ===== Pirin’s nuclear activity under [[oxidative stress]] orchestrates a self-sustaining inflammatory loop that drives HCC, suggesting a novel antioxidant-modifiable target for [[tumor suppression]]. ===== Citation ===== Nuclear Pirin promotes HCC by acting as a key inflammation-facilitating factor. Ma H, et al. *Gut.* Published online June 27, 2025. doi:10.1136/gutjnl‑2024‑334087. Corresponding authors: Qinxi Li (liqinxi@xmu.edu.cn), Weiling He (wlhe@xah.xmu.edu.cn)