{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:07:05Z","timestamp":1789020425073,"version":"build-2803163510"},"reference-count":112,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"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. Cell Dev. Biol."],"abstract":"<jats:p>Mitogen-activated protein kinase kinase 20 (MAP3K20\/ZAK) has emerged as a critical biophysical sensor, uniquely poised at the intersection of environmental stress and cellular fate. Its versatile signaling is primarily orchestrated by two structurally distinct splice variants: ZAK\u03b1, which drives the ribotoxic stress response (RSR) upon detecting ribosome collisions, and ZAK\u03b2, which mediates homeostatic mechanotransduction. However, emerging evidence indicates that the biological roles of ZAK cannot be strictly categorized as either pathogenic or protective. It exhibits profound functional plasticity and engages non-canonical metabolic networks in a highly context-dependent manner. Consequently, dysregulated ZAK signaling acts as a powerful disease amplifier across diverse human pathologies, including aggressive malignancies, cardiac remodeling, systemic metabolic deterioration, and inherited myopathies. While targeting ZAK presents a compelling therapeutic opportunity, current broad-spectrum kinase inhibitors are heavily confounded by \u201con-target, off-tissue\u201d toxicities, particularly within the epidermal barrier. In this review, we synthesize the structural mechanisms, downstream cascades, and complex pathobiology of ZAK. Furthermore, we discuss an emerging Frontier in ZAK pharmacology: the conceptual development of structure-guided, isoform-selective allosteric interventions designed to safely decouple pathogenic ZAK\u03b1 signaling from essential ZAK\u03b2-mediated tissue homeostasis.<\/jats:p>","DOI":"10.3389\/fcell.2026.1909993","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:31:55Z","timestamp":1789018315000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ZAK kinase at the crossroads of cellular stress: functional plasticity, human pathobiology, and precision therapeutics"],"prefix":"10.3389","volume":"14","author":[{"given":"Yeteng","family":"Xiong","sequence":"first","affiliation":[{"name":"The First School of Clinical Medicine, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Public Health, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Huang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingnan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Public Health, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanchuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Guangdong Provincial Key Laboratory of Single Cell and Extracellular Vesicles, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1101\/gad.237206.113","article-title":"An integrative analysis of Colon cancer identifies an essential function for PRPF6 in tumor growth","volume":"28","author":"Adler","year":"2014","journal-title":"Genes Dev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/nrd1343","article-title":"Small-molecule inhibitors of protein-protein interactions: progressing towards the dream","volume":"3","author":"Arkin","year":"2004","journal-title":"Nat. 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