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The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1\u03b1), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1\u03b1 in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.<\/jats:p>","DOI":"10.3390\/ijms241311105","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T00:34:30Z","timestamp":1688603670000},"page":"11105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches"],"prefix":"10.3390","volume":"24","author":[{"given":"Esmaa","family":"Bouhamida","sequence":"first","affiliation":[{"name":"Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampaolo","family":"Morciano","sequence":"additional","affiliation":[{"name":"Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy"},{"name":"Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4620-4063","authenticated-orcid":false,"given":"Gaia","family":"Pedriali","sequence":"additional","affiliation":[{"name":"Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1160-7599","authenticated-orcid":false,"given":"Daniela","family":"Ramaccini","sequence":"additional","affiliation":[{"name":"Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Tremoli","sequence":"additional","affiliation":[{"name":"Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2494-7405","authenticated-orcid":false,"given":"Carlotta","family":"Giorgi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7108-6508","authenticated-orcid":false,"given":"Paolo","family":"Pinton","sequence":"additional","affiliation":[{"name":"Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy"},{"name":"Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7951-9267","authenticated-orcid":false,"given":"Simone","family":"Patergnani","sequence":"additional","affiliation":[{"name":"Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy"},{"name":"Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1242\/dmm.006510","article-title":"Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition","volume":"4","author":"Aisagbonhi","year":"2011","journal-title":"Dis. 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