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Soluble guanylyl cyclase (sGC), the main NO receptor composed of the sGC\u03b11 and sGC\u03b21 subunits, has been one of the central figures in this narrative. However, the sGC\u03b11 and sGC\u03b21 subunits remained obscured by the focus on sGC\u2019s enzymatic activity for many years. In this review, we restore the significance of the sGC\u03b11 and sGC\u03b21 subunits by compiling and analyzing available but previously overlooked information regarding their roles beyond enzymatic activity. We delve into the basics of sGC expression regulation, from its transcriptional regulation to its interaction with proteins, placing particular emphasis on evidence thus far demonstrating the actions of each sGC subunit in different tumor models. Exploring the roles of sGC subunits in cancer offers a valuable opportunity to enhance our understanding of tumor biology and discover new therapeutic avenues.<\/jats:p>","DOI":"10.3390\/ijms251810053","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T03:34:20Z","timestamp":1726716860000},"page":"10053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Challenging the Norm: The Unrecognized Impact of Soluble Guanylyl Cyclase Subunits in Cancer"],"prefix":"10.3390","volume":"25","author":[{"given":"Mar\u00eda Teresa L.","family":"Pino","sequence":"first","affiliation":[{"name":"Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET\u2013Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Victoria","family":"Rocca","sequence":"additional","affiliation":[{"name":"Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET\u2013Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas H.","family":"Acosta","sequence":"additional","affiliation":[{"name":"Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET\u2013Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimena P.","family":"Cabilla","sequence":"additional","affiliation":[{"name":"Centro de Altos Estudios en Ciencias Humanas y de la Salud, CONICET\u2013Universidad Abierta Interamericana, Buenos Aires C1270AAH, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5839","DOI":"10.1073\/pnas.1804932115","article-title":"Oxygen Radicals, Nitric Oxide, and Peroxynitrite: Redox Pathways in Molecular Medicine","volume":"115","author":"Radi","year":"2018","journal-title":"Proc. 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