{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:27:26Z","timestamp":1785421646336,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tsumura & 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>Major depressive disorder (MDD) lacks reliable laboratory tests for diagnosis and treatment monitoring, underscoring the need for robust molecular readouts in blood. Beyond symptom-based classification, MDD can also be viewed as a condition involving impaired homeostatic regulation across stress-responsive, immune, metabolic, and neural systems. Consistent with this perspective, altered intron retention (IR) patterns have been observed in peripheral blood in depression-related and treatment-response contexts, supporting the translational relevance of this RNA-processing layer to mood disorders. A key observation underpinning this review is that IR can function as a reversible, intervention-responsive readout of physiological state. In a pre-symptomatic stress-like state in klotho mutant mice (a premature-aging model), widespread IR increases revert toward a healthy pattern upon treatment, suggesting that IR is embedded in a controllable homeostatic layer. Against the backdrop of limited cross-cohort transferability of differential gene expression (DGE) signatures, we propose that IR provides a mechanistically grounded biomarker layer because it reports regulated RNA processing states rather than context-fragile abundance endpoints. We operationalize IR as a post-transcriptional \u201cthrottle\u201d on effective gene output, with increased IR\/detained intron (DI) states acting as a reversible brake and decreased IR acting as an accelerator that increases translation-competent mRNA supply. Mechanistic exemplars across immune, metabolic, and neuronal systems (e.g., IFNG, OGT, MAT2A, neuronal activity-triggered intron excision, and intron detention-mediated stemness\/differentiation switching in adult neural stem cells) show that defined inputs can switch IR\/DI states to tune output kinetics. Integrating these findings, we propose an \u201cIntron Retention Homeostat\u201d (IR-Homeostat) model in which cells sense deviations from physiological set points and implement feedback control of gene output through switchable IR\/DI regulation. This framework positions IR not only as a robust state readout for stratification, treatment response prediction, and pharmacodynamic profiling, but also as a tractable entry point to identify the molecular sensors and mediators that couple homeostatic signals to RNA processing control.<\/jats:p>","DOI":"10.3390\/ijms27073119","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:11:59Z","timestamp":1774872719000},"page":"3119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The IR-Homeostat Hypothesis: Intron Retention as an Evolutionarily Conserved Fine-Tuning Layer and a Reversible Blood Biomarker of Homeostatic Dysregulation in Mood Disorders"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3655-8060","authenticated-orcid":false,"given":"Norihiro","family":"Okada","sequence":"first","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"}]},{"given":"Kenshiro","family":"Oshima","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":[[2026,3,30]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2017). 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