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Quiescent HSCs express the NO\u2010cGMP signalling axis. Modulating this pathway could alter HSC activation and fibrosis during MASH progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Using transgenic cGMP sensor mice, we monitored NO\u2010induced cGMP in living HSCs. The relevance of this pathway was analyzed using HSC\u2010specific mouse models, ApoE\u2010deficient mice on high\u2010fat diet as a MASH model, human liver sections, and published scRNA\u2010seq datasets. For pharmacological activation of NO\u2010cGMP signalling, BAY\u2010543, an activator of NO\u2010sensitive guanylyl cyclase (NO\u2010GC) was used.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>HSCs in primary culture and liver tissue generated NO\u2010induced cGMP and expressed NO\u2010GC and cGMP\u2010dependent protein kinase type I (cGKI). Compared to controls, HSC\u2010specific cGKI knockout livers showed enhanced myofibroblast marker expression, indicating increased HSC activation and MASH susceptibility. MASH mice developed steatosis, fibrosis, and inflammation, and showed a high number of HSCs expressing NO\u2010GC and cGKI. cGKI expression was also increased in human fibrotic livers as compared to healthy tissue. In MASH livers, oxidative stress could lead to reduced sensitivity of NO\u2010GC to NO. Treatment of MASH mice with BAY\u2010543, which targets oxidized\/NO\u2010insensitive NO\u2010GC, significantly attenuated HSC activation, inflammation, collagen deposition, macro\u2010steatosis, fibrosis, and serum liver enzymes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>The NO\u2010cGMP\u2010cGKI axis serves as both a functional pathway marker and regulator of HSCs. Pharmacological elevation of cGMP with an NO\u2010GC activator represents a promising therapeutic strategy for MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70523","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:11:42Z","timestamp":1782432702000},"page":"5476-5495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological activation of NO\u2010cGMP signalling attenuates metabolic dysfunction\u2010associated steatohepatitis"],"prefix":"10.1111","volume":"183","author":[{"given":"Krithika","family":"Rajeeth","sequence":"first","affiliation":[{"name":"Interfaculty Institute of Biochemistry University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Roessing","sequence":"additional","affiliation":[{"name":"Interfaculty Institute of Biochemistry University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Lehners","sequence":"additional","affiliation":[{"name":"Interfaculty Institute of Biochemistry University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Dietz","sequence":"additional","affiliation":[{"name":"Cardiovascular Research, Pharma Research Centre Bayer AG  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Medicine A, Hematology, Oncology, and Pneumology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Hailfinger","sequence":"additional","affiliation":[{"name":"Department of Medicine A, Hematology, Oncology, and Pneumology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Peter","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Pathobiochemistry University Hospital T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Diabetes Research (DZD e.V.)  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