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CRS has become a global threat, with high disease\u2010associated illness and mortality rates having a significant impact on the healthcare system. Kidney diseases also share various mechanisms involved in the pathogenesis of cardiac dysfunction. The current treatment strategies for CRS mainly focus on symptomatic relief rather than disease mitigation. In recent years, research has been performed to explore the potential targets in managing CRS. In this review, the literature evaluation of different signaling mechanisms including Wnt\/\u03b2\u2010catenin, cyclic guanosine monophosphate (cGMP)\u2010 adenosine monophosphate (AMP) synthase stimulator of interferon genes (cGAS\/STING), NOD\u2010like receptor pyrin domain\u2010containing 3 (NLRP3) inflammasome, mitogen\u2010activated protein kinase (MAPK) pathway, apoptosis signal\u2010regulating kinase 1 (ASK1) pathway, histone deacetylase (HDAC), peroxisome proliferator\u2010activated receptor gamma coactivator 1 alpha (PGC1\u03b1), \u03b1\u2010klotho, fibroblast growth factor 23 (FGF\u201023), and oxidative damage concerning the pathophysiological aspects of CRS were discussed. We highlighted a few new emerging pathways with a protective role, some with a disease\u2010progressive role, and some with a diversified role in CRS. This scientific review can help researchers identify promising treatment strategies to manage CRS. As stated in this review, these pathways can be the basis for introducing potential inhibitor molecules of disease\u2010progressing targets. Also, this scientific review will help identify molecules with agonistic properties as a protective way to transform current treatment strategies into more specific, effective treatment strategies against CRS with minimum side effects.<\/jats:p>","DOI":"10.1002\/jbt.70409","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T11:15:57Z","timestamp":1753960557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deciphering the Emerging Signaling Pathways That Interplay Between Chronic Kidney Disease and Heart: Therapeutic Challenges and Opportunities"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7506-4725","authenticated-orcid":false,"given":"Puneet","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research \u2010Guwahati Changsari Assam India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7409-3444","authenticated-orcid":false,"given":"Ch. 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