{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:54:33Z","timestamp":1790189673983,"version":"4.1.0"},"reference-count":124,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The NLRP3 inflammasome, a pivotal component of innate immunity, orchestrates immune defense and inflammatory responses. NEK7, an essential upstream regulator, drives inflammasome assembly through direct interaction with NLRP3. This review systematically summarizes the molecular mechanisms, upstream regulatory networks, and therapeutic targeting of the NEK7-NLRP3 axis. Structurally, NEK7 binds to the leucine-rich repeat (LRR) domain of NLRP3 via its catalytic domain, inducing conformational rearrangement and oligomerization. This structural shift exposes NLRP3\u2019s PYRIN domain (PYD), enabling ASC recruitment through homotypic PYD-PYD interactions and subsequent pro-caspase-1 activation to form the mature inflammasome complex. At the regulatory level, cell cycle-dependent NEK7 availability, post-translational modifications (phosphorylation\/ubiquitination\/palmitoylation), and numerous upstream signals\u2014including kinases, ubiquitin ligases, ionic fluxes, miRNAs, and pathogens\u2014collectively fine-tune the NEK7-NLRP3 interaction. In terms of therapeutic targeting, natural compounds from traditional Chinese medicine (e.g., oridonin, pristimerin), synthetic inhibitors (e.g., MCC950, entrectinib), and biological agents have been shown to suppress inflammasome activation by disrupting the NEK7-NLRP3 interface or modulating associated regulatory pathways. These advances offer novel therapeutic strategies for NLRP3-driven pathologies including gouty arthritis, ischemia-reperfusion injury, neurodegenerative disorders, and metabolic syndromes.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1773422","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:21:30Z","timestamp":1776140490000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Deciphering the NEK7-NLRP3 inflammasome assembly: from conformational activation to allosteric drug discovery"],"prefix":"10.3389","volume":"17","author":[{"given":"Chun-Ling","family":"Gu","sequence":"first","affiliation":[{"name":"Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Dong","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences","place":["Beijing, China"]},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hong","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Cai","family":"Shang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]},{"name":"Dongfang Hospital, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.12182\/20230560105","article-title":"Latest findings on nod-like receptor family pyrin domain containing protein 3 inflammasome and bone and articular diseases","volume":"54","author":"Wang","year":"2023","journal-title":"Sichuan Da Xue Xue Bao Yi Xue Ban"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/liv.16234","article-title":"Inhibition of Ire-1alpha alleviates pyroptosis and metabolic dysfunction-associated steatohepatitis by suppressing gasdermin D","volume":"45","author":"Zeng","year":"2025","journal-title":"Liver Int"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00740-6","article-title":"Nlrp3 inflammasome activation and cell death","volume":"18","author":"Huang","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7246","DOI":"10.1038\/s41467-023-43180-8","article-title":"Cryo-electron tomography of Nlrp3-activated Asc complexes reveals organelle co-localization","volume":"14","author":"Liu","year":"2023","journal-title":"Nat Commun"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1188864","article-title":"What are Nlrp3-Asc specks? 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