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Improved understanding of mechanisms underlying transition from early-stage DbCM to HFpEF will inform innovative evidence-based treatment approaches, which are urgently required to alleviate increasing disease burden. This study aimed to determine whether inhibition of neprilysin activity by Sacubitril\/Valsartan in both experimental and clinical DbCM attenuates adverse remodelling through promotion of cardioprotective signalling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and results<\/jats:title>\n            <jats:p>Sacubitril\/Valsartan effectively reduced plasma neprilysin activity in both diabetic patients with pre-clinical HFpEF from the PARABLE trial (baseline (Val n\u2009=\u200925; Sac\/Val n\u2009=\u200935) and 3\u00a0months after treatment (Val n\u2009=\u200921\/25; Sac\/Val n\u2009=\u200933\/35)) and DbCM (high-fat diet and streptozotocin) mice. Plasma neprilysin activity at baseline was correlated with worsening cardiac performance at 18\u00a0months indicated by left atrial stiffness index in patients (n\u2009=\u200944\/60), whilst diastolic dysfunction and pathological remodelling in DbCM mice were improved by Sacubitril\/Valsartan, but not Valsartan. snRNA-sequencing showed that progressive experimental DbCM is characterised by chronic low-grade inflammation, reflected by increased infiltration of pro-inflammatory monocytes (Ccr2<jats:sup>+<\/jats:sup> Ly6c<jats:sup>hi<\/jats:sup>) and reduction in MHC-II macrophages, which was prevented by Sacubitril\/Valsartan. Informatics analysis implicated <jats:italic>IRF7<\/jats:italic> as a central mediator of Sacubitril\/Valsartan-induced immunomodulation in DbCM, whilst treatment of M2-like pro-repair macrophages with the neprilysin inhibitor, LBQ657 and Valsartan suppressed glucose-induced <jats:italic>IRF7<\/jats:italic> expression and paracrine activation of cardiac fibroblast differentiation in vitro.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Immune cells are significantly involved in DbCM progression, impacting myocardial homeostasis and HF progression. Neprilysin inhibition by Sacubitril\/Valsartan improved adverse cardiac remodelling in experimental DbCM through direct regulation of inflammation, highlighting immunomodulation as a novel mechanism underlying established its cardioprotective actions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1186\/s12933-025-02741-5","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T17:58:07Z","timestamp":1747245487000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sacubitril\/Valsartan attenuates progression of diabetic cardiomyopathy through immunomodulation properties: an opportunity to prevent progressive disease"],"prefix":"10.1186","volume":"24","author":[{"given":"Narainrit","family":"Karuna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Kerrigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Edgar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Ledwidge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Grieve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J.","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"2741_CR1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.diabres.2018.02.023","volume":"138","author":"NH Cho","year":"2018","unstructured":"Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. 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