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It accounts for at least half of all heart failure cases and is associated with substantial morbidity and mortality. Although the prevalence of HFpEF increases with age, a substantial proportion of the HFpEF subjects present with cardiometabolic alterations, marking a specific phenogroup of HFpEF. Obesity, diabetes, and hypertension are considered central features in the pathophysiology of HFpEF, driving its development and disease progression by a complex interplay of metabolic-, hemodynamic-, and neurohormonal impairments, resulting in systemic inflammation and immune system dysregulation. Cellular and systemic immunometabolic stress induces vascular endothelial microvascular dysfunction, infiltration of immune cells in the myocardium, and activation of innate and adaptive immune cells in cardiac tissue. The resulting bidirectional crosstalk between systemic and cardiac metabolism influences immune cell reprogramming, sustaining a vicious cycle of cardiac chronic inflammatory response, ultimately leading to adverse structural and functional cardiac remodeling. In this review, we discuss the role of cellular interactions and immunometabolic mechanisms of immune system dysregulation resulting in cardiometabolic HFpEF and elaborate on therapeutic strategies targeting cardiometabolic risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.125.012674","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T10:00:14Z","timestamp":1770026414000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Cellular Interactions and Immunometabolic Mechanisms in Heart Failure With Preserved Ejection Fraction: From Molecular Mechanisms to Clinical Evidence"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-5865","authenticated-orcid":true,"given":"Alexander","family":"Peikert","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Heart Center Graz (A.P.), Medical University of Graz, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0051-7723","authenticated-orcid":true,"given":"Antonio","family":"Vacca","sequence":"additional","affiliation":[{"name":"Clinica Medica, Department of Medicine, University of Udine, Italy (A.V.)."},{"name":"Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany (A.V., G.G.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6081-1257","authenticated-orcid":true,"given":"Giuseppe D.","family":"Norata","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences (DisFeB), Universit\u00e0 Degli Studi di Milano, Italy 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