PIWIL2 drives stroke progression via modulation of NF-κB signaling.

Overview

Authors: Rohan Mahesh Patil^1,2, Giusy Laudati¹, Natascia Guida¹, Silvia Ruggiero¹, Noemi Di Muraglia¹, Serenella Anzilotti³, Julian Lanthaler¹, Luigi Coppola⁴, Luigi Formisano¹, Lucio Annunziato⁴, Elga Esposito², Giuseppe Pignataro¹

ORCID iDs: Giuseppe Pignataro

Division of Pharmacology, Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, 80131 Naples, Italy
Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Department for the Promotion of Human Sciences and Quality of Life, San Raffaele University, 00166 Rome, Italy
IRCCS SDN Naples, Via Gianturco 113 80143 Naples, Italy

Institutions: Harvard University (United States); Massachusetts General Hospital (United States); University of Naples Federico II (Italy); San Raffaele University of Rome (Italy); SDN Istituto di Ricerca Diagnostica e Nucleare (Italy)

Journal: Molecular therapy. Nucleic acids, volume 37, issue 3, article 103037

Dates: received 15 August 2025; accepted 22 July 2026; published online 24 July 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1016/j.omtn.2026.103037 · PMID 42621097 · PMCID PMC13486804 · OpenAlex W7170243439

Open access: gold, a free copy (OpenAlex)

Status: code on request

Categories: stroke (population), cellular / molecular (subfield)

Methods: Spectral & time-frequency, Statistics

Keywords: MT: non-coding RNAs, PIWIL, brain inflammation, ischemic stroke, blood brain barrier, systemic role, RNA binding protein, chemokine response, NF-kB

Topic: NF-κB Signaling Pathways (Cancer Research, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: Ministero della Salute; Regione Campania; Ministero dell'Istruzione e del Merito

Citations: not cited yet (Europe PMC); 36 references in the paper

Abstract

PIWILs are RNA-binding proteins whose role in ischemic stroke remains poorly defined. Here, we investigated the contribution of PIWILs to post-ischemic neuroinflammation by using a mouse model of 1 h transient middle cerebral artery occlusion (tMCAo), followed by 6 or 24 h of reperfusion. Brain tissues, blood, and peripheral organs were collected to assess PIWIL expression, inflammatory responses, and brain damage. PIWIL1 and PIWIL2 were significantly upregulated in the cortex and striatum at 24 h post-ischemia, with PIWIL2 also increased in blood and peripheral tissues. Immunofluorescence analyses revealed cell-type-specific localization of PIWILs in neurons, astrocytes, and endothelial cells. Notably, siRNA-mediated silencing of PIWIL2 significantly reduced infarct volume. PIWIL2 silencing also attenuated NF-κB-p65 and phospho-IκBα levels in the peri-infarct cortex but not in the striatum, indicating region-specific modulation of NF-κB signaling and differentially reprogrammed systemic chemokine profiles, with selective upregulation of CCL3, CCL5, and CXCL13 and downregulation of CCL2, CCL17, CCL20, and CXCL1. Mechanistically, PIWIL2 interacted with IKKα and promoted activation of the NF-κB pathway, leading to RelA- and RelB-dependent transcriptional regulation of pro-inflammatory chemokines. Together, these findings identify PIWIL2 as an upstream regulator of NF-κB-dependent neuroinflammation that exacerbates ischemic brain injury and suggest PIWIL2 as a promising therapeutic target targeting post-stroke inflammatory damage.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

Funding: added Ministero della Salute; Regione Campania; Ministero dell'Istruzione e del Merito

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 9 keywords, 35 references.

Cite

This paper

Patil, R. M., Laudati, G., Guida, N., Ruggiero, S., Di Muraglia, N., Anzilotti, S., Lanthaler, J., Coppola, L., Formisano, L., Annunziato, L., Esposito, E., & Pignataro, G. (2026). PIWIL2 drives stroke progression via modulation of NF-κB signaling. Molecular therapy. Nucleic acids, 37(3), 103037. https://doi.org/10.1016/j.omtn.2026.103037

BibTeX

@article{patil2026piwil2, author = {Patil, Rohan Mahesh and Laudati, Giusy and Guida, Natascia and Ruggiero, Silvia and Di Muraglia, Noemi and Anzilotti, Serenella and Lanthaler, Julian and Coppola, Luigi and Formisano, Luigi and Annunziato, Lucio and Esposito, Elga and Pignataro, Giuseppe}, title = {{PIWIL2 drives stroke progression via modulation of NF-κB signaling}}, journal = {Molecular therapy. Nucleic acids}, year = {2026}, month = jul, volume = {37}, number = {3}, pages = {103037}, publisher = {American Society of Gene \& Cell Therapy}, issn = {2162-2531}, doi = {10.1016/j.omtn.2026.103037}, url = {https://doi.org/10.1016/j.omtn.2026.103037}, pmid = {42621097}, pmcid = {PMC13486804} }

RIS

TY - JOUR AU - Patil, Rohan Mahesh AU - Laudati, Giusy AU - Guida, Natascia AU - Ruggiero, Silvia AU - Di Muraglia, Noemi AU - Anzilotti, Serenella AU - Lanthaler, Julian AU - Coppola, Luigi AU - Formisano, Luigi AU - Annunziato, Lucio AU - Esposito, Elga AU - Pignataro, Giuseppe TI - PIWIL2 drives stroke progression via modulation of NF-κB signaling T2 - Molecular therapy. Nucleic acids J2 - Mol Ther Nucleic Acids PY - 2026 DA - 2026/07/24 VL - 37 IS - 3 SP - 103037 SN - 2162-2531 PB - American Society of Gene & Cell Therapy DO - 10.1016/j.omtn.2026.103037 UR - https://doi.org/10.1016/j.omtn.2026.103037 LA - en ER -

CSL-JSON

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