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In this review, we elucidate emerging mechanisms that govern the transition from acute inflammation to pathological fibrosis, with particular focus on cellular crosstalk between neutrophils, macrophages, fibroblasts, and myofibroblasts. We explore how dysregulated immune responses and extracellular matrix (ECM) remodeling sustain a pathogenic feedback loop, promoting myocardial stiffening and adverse cardiac remodeling. Special attention is given to the plasticity of immune and stromal cells, including macrophage polarization and fibroblast\u2010to\u2010myofibroblast transitions, as well as the roles of TGF\u2010\u03b2 signaling, hypoxia, and noncoding RNAs. Building on this mechanistic foundation, we highlight next\u2010generation therapeutic strategies\u2014ranging from immunometabolic and epigenetic reprogramming to gene editing, cell\u2010based therapies, and nanomedicine\u2014designed to interrupt the inflammation\u2013fibrosis axis. By targeting these interconnected pathways, emerging therapies offer the potential to reverse maladaptive remodeling, restore cardiac function, and redefine the treatment landscape in cardiovascular disease.<\/jats:p>","DOI":"10.1096\/fj.202500970r","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T09:00:16Z","timestamp":1757408416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Targeting Inflammation and Fibrosis in Cardiovascular Disease: Emerging Mechanisms and Therapies"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8502-7098","authenticated-orcid":false,"given":"Hector A.","family":"Cabrera\u2010Fuentes","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Estudios de Posgrado e Investigaci\u00f3n Tecnol\u00f3gico Nacional de M\u00e9xico\/Instituto Tecnol\u00f3gico de Tijuana  Tijuana M\u00e9xico"},{"name":"R&amp;D Group, 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