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We set out to discover potentially druggable regulators of HSF1 activation and identified DEAH-box RNA helicase 8 (DHX8). We investigated the role of DHX8 in regulating HSF1 within the broader context of DHX8 function in cancer cells. DHX8 silencing induces intron retention in HSF1 transcripts, reducing HSF1 protein. Importantly, DHX8 loss significantly alters RNA processing of an HSF1-regulated cancer-associated gene signature linked to poor clinical outcomes, as well as additional oncogenic and stress-response pathways. DHX8 binds between the pre-messenger RNA (mRNA) lariat branch point and the 3\u2032 splice site, consistent with the predominance of intron-retained transcripts following DHX8 loss. We show that both the ATPase and RNA-binding activities of DHX8 are essential for its role in splicing, including processing of\u00a0HSF1 mRNA. We also find that DHX8 silencing triggers apoptosis more effectively in human cancer cells than in non-tumorigenic cells. Our findings identify DHX8 as a critical regulator of stress-adaptive gene expression, highlighting its promise as a therapeutic target not only to disrupt HSF1-dependent transcriptional programs but also having broader effects in cancer cells under oncogenic stress.<\/jats:p>","DOI":"10.1093\/narcan\/zcag008","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T12:23:02Z","timestamp":1771849382000},"source":"Crossref","is-referenced-by-count":1,"title":["Human DEAH-box helicase 8 regulates HSF1-mediated stress response and cancer-associated pre-mRNA splicing in tumour cells"],"prefix":"10.1093","volume":"8","author":[{"given":"Jennifer R","family":"Tall","sequence":"first","affiliation":[{"name":"Centre for Cancer Drug Discovery, Division of Cancer Therapeutics, The Institute of Cancer Research , London SM2 5GP ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert 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