{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:16:13Z","timestamp":1785417373550,"version":"3.56.0"},"reference-count":64,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tsumura and Co."},{"id":[{"id":"https:\/\/ror.org\/02r19bt50","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clinically robust molecular biomarkers for depression have remained elusive, despite extensive transcriptomic research. This gap is consequential: depression is prevalent and heterogeneous, yet objective measures to quantify burden, stratify patients, and track recovery remain limited. Here, we review evidence that intron retention (IR) can serve as a homeostatic state variable\u2014and therefore a sensitive biomarker\u2014reporting stress adaptation and recovery at an upstream regulatory layer, often preceding or outperforming differential gene expression (DEG) readouts. Mechanistically, IR enables bidirectional fine-tuning of effective gene output: increased IR (IncIR) can throttle output under overload, whereas decreased IR (DecIR) releases this brake to restore gene output. Because these shifts are reversible and treatment-responsive, IR signatures can function not only as disease markers but also as pharmacodynamic metrics for blood-based monitoring of drug response and recovery. To evaluate the clinical utility of IR, we use depression as a proof of concept and focus on two interventions: (i) the Kampo formula hangekobokuto (HKT), which is associated with IR normalization consistent with reduced peripheral inflammatory load; and (ii) ketamine, where IR patterns measured before ketamine treatment in non-responders are linked to stronger innate-immune\/antiviral activity, suggesting a higher inflammatory load that may limit treatment benefit. Finally, we discuss transdiagnostic extensions beyond depression, using early cognitive decline (mild cognitive impairment, MCI) as a stringent, biologically distal test case for blood-based IR\/DI readouts and motivating independent cohort replication and longitudinal validation.<\/jats:p>","DOI":"10.3390\/ijms27083539","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T07:37:19Z","timestamp":1776325039000},"page":"3539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intron Retention as a Homeostatic State Variable for Drug Response and Recovery: Lessons from Depression for Broader Applications"],"prefix":"10.3390","volume":"27","author":[{"given":"Norihiro","family":"Okada","sequence":"first","affiliation":[{"name":"School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenshiro","family":"Oshima","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Maruko","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0495-3023","authenticated-orcid":false,"given":"Akinori","family":"Nishi","sequence":"additional","affiliation":[{"name":"TSUMURA Advanced Technology Research Laboratories, Research & Development Division, TSUMURA & Co., Ibaraki 300-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4289-7392","authenticated-orcid":false,"given":"Yoshinori","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"},{"name":"Oriental Medicine Research Center, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Okada, N., Maruko, A., Oshima, K., Nishi, A., and Kobayashi, Y. 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