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Structurally characterized by its thioredoxin\u2010binding domain, its kinase domain, and coiled\u2010coil structures, ASK1 relays downstream stimulation of JNK and p38 MAPK cascades. Yet, its role in cancer function is paradoxical and simultaneously serves as both a cancer inhibitor and an activator rely on cellular settings. In this article, an overview of the molecular biology of ASK1 is presented with emphasis on the elusive balance between stimulation and suppression by upstream molecules such as Trx, TRAF proteins, and ubiquitination machinery. We provide an overview of the dualistic role of ASK1 in cancer pathophysiology showing how its dysregulation leads to tumor development, metastasis, chemoresistance, or tumor suppression by pro\u2010apoptotic signals, respectively. An example of context\u2010dependent action is provided using the examples of different cancers including lung, breast, ovarian, and hepatocellular carcinoma. Moreover, we discuss new therapeutic approaches to ASK1 such as small\u2010molecule inhibitors, RNA therapies, and protein\u2010protein interaction modulation and speculate on their potential in personalized medicine. The article also deals with future opportunities in the sense of the bivalent character of ASK1 in developing context\u2010dependent and targeted cancer therapies. The key to unlocking the potential of ASK1 to be used as a therapeutic intervention and overcome the complications that are posed by its dualistic nature in cancer biology lie in the understanding of the complex regulatory network it forms.<\/jats:p>","DOI":"10.1002\/jbt.70605","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T08:25:16Z","timestamp":1762763116000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["ASK1 Signaling in Cancer: Pathogenic Driver or Therapeutic Target?"],"prefix":"10.1002","volume":"39","author":[{"given":"Yumna","family":"Khan","sequence":"first","affiliation":[{"name":"Institute of Biotechnology and Genetic Engineering (Health Division) The University of Agriculture Peshawar 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Saveetha Medical College Saveetha Institute of Medical and Technical Sciences, Saveetha University Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Gupta","sequence":"additional","affiliation":[{"name":"Centre for Research Impact &amp; Outcome\u2010Chitkara College of Pharmacy Chitkara University Rajpura Punjab India"},{"name":"Centre of Medical and Bio\u2010allied Health Sciences Research, Ajman University Ajman UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3554-1750","authenticated-orcid":false,"given":"Md Sadique","family":"Hussain","sequence":"additional","affiliation":[{"name":"Uttaranchal Institute of Pharmaceutical Sciences Uttaranchal University Dehradun Uttarakhand 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