BACKGROUND: Fibrocalcific aortic valve disease (FCAVD) is a progressive and multifactorial pathology that remains asymptomatic in its early stages and lacks effective pharmacological therapies. Aortic valve sclerosis (AVSc), the initial phase of FCAVD, is marked by leaflet thickening and early calcium deposition without significant hemodynamic changes. While local inflammation is known to drive valvular remodeling, recent studies suggest that systemic inflammation may also play a critical role, potentially interacting with endothelial (VEC) and interstitial cells (VIC) and thus promoting disease progression. Notably, sex differences in fibrocalcific processes have been identified, yet their mechanistic basis remains understudied. Thus, we hypothesize that systemic inflammation exacerbates endothelial dysfunction and accelerates fibrocalcific remodeling, with distinct processes in men and women, and aim to investigate how these mechanisms contribute to disease progression. METHODS: A total of 238 individuals were enrolled across three groups: controls (CTRL n = 80), AVSc (n = 78), and severe aortic stenosis (AS n = 80). A broad panel of circulating cytokines was measured and analyzed with respect to sex and disease stage. To assess the functional impact of key cytokines, in vitro experiments were conducted using human VECs and VICs treated with interleukin-1β (IL-1β) and interferon-β (IFNβ). Cellular responses were evaluated via morphological analyses, gene and protein expression assays, and calcification potential under normal and pro-osteogenic conditions. RESULTS: Cytokine profiling revealed that AVSc patients exhibited significantly elevated levels of IL-1β compared to both CTRL and AS, with IL-1β being consistently higher in males across all stages. In vitro, IL-1β triggered endothelial-to-mesenchymal transition in VECs, promoting a pro-fibrotic and inflammatory phenotype. Sex-stratified analysis of VICs showed that IFNβ enhanced RUNX2 expression and calcification in a dose-dependent manner, with female-derived VICs being more responsive. Conversely, IFNβ exerted anti-fibrotic effects by reducing COL1A1 and ACTA2 expression, more markedly in female cells, particularly at the protein level. CONCLUSION: Our findings reveal a previously overlooked role of systemic inflammation, primarily driven by IL-1β and IFNβ, in promoting early endothelial activation and sex-specific fibrocalcific remodeling in FCAVD. These cytokines not only serve as markers of disease but also actively influence cell-specific responses, shaping the distinct aortic valve fibrocalcific patterns observed in men and women. Unraveling these mechanisms could open new avenues for developing early monitoring of circulating IL-1β and IFNβ, while informing sex-specific therapeutic strategies to modulate cytokine signaling to slow or prevent FCAVD progression.