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Activating Transcription Factor 6 (ATF6) controls a key UPR branch and upregulates genes that mitigate ER stress. Small molecule modulators of ATF6 have been characterized in cell culture models that increase or decrease the amount of the cleaved, transcriptional activator domain of ATF6 generated from the full\u2010length precursor. However, the effects of these small molecule ATF6 modulators remain unclear in\u00a0vivo, in part because of the lack of antibodies that robustly detect the cleaved, activated form of ATF6 in model organisms like mice. Here, we used targeted RNA sequencing (RNA\u2010seq) to assess the transcriptional response to intraocular delivery of Ceapin\u2010A7 (an ATF6 inhibitor) and AA147 (an ATF6 activator) in the mouse retina. Using this strategy, we demonstrate that Ceapin\u2010A7 significantly suppressed ATF6 transcriptional targets, whereas AA147 induced ATF6\u2010regulated genes in retinal tissue of the eye. We also show that neither small molecule ATF6 modulator caused retinal cell death, compromised vision, or triggered ER stress by histology, functional testing, and transcriptional analysis. These results identify a transcriptional strategy to sensitively detect and quantify Ceapin\u2010A7 and AA147 modulation of ATF6 in\u00a0vivo. These findings also identify nontoxic conditions for further in\u00a0vivo evaluation of small molecule ATF6 modulators in mouse vision loss disease models linked to ER stress.<\/jats:p>","DOI":"10.1096\/fj.202501459r","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T12:44:37Z","timestamp":1755607477000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Transcriptomic Profiling of Small Molecule Atf6 Modulators in the Retina"],"prefix":"10.1096","volume":"39","author":[{"given":"Monica Sophia","family":"Diaz\u2010Aguilar","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Stanford University  Stanford California USA"},{"name":"VA Palo Alto Healthcare System  Palo Alto California USA"},{"name":"Department of Pathology Stanford University  Stanford California USA"},{"name":"Doctor of Medicine Program Rush University Medical College  Chicago Illinois 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