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Introduction Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a progressive fibrotic disorder and a leading cause of mortality in systemic sclerosis. Endothelial dysfunction is a key feature of SSc-ILD, but the molecular mechanisms remain poorly understood. Receptor-interacting protein kinase 3 (RIPK3) is involved in inflammation and cell death, but its role in endothelial cells during SSc-ILD is unknown. Our recent analysis of publicly available datasets shows that RIPK3 is elevated in both SSc-ILD patient samples (GSE58095) and murine models (GSE199581), highlighting its potential relevance to disease progression. We hypothesized that endothelial-specific RIPK3 compromises vascular barrier integrity, contributing to SSc-ILD progression.Material and Methods Ripk3fl/fl mice were crossed with Cdh5(PAC)-CreERT2 mice to generate Ripk3fl/fl;iCdh5(PAC)-CreERT2 mice (Ripk3iECKO). Ripk3fl/fl littermates served as controls (Ripk3WT). Male (M) and female (F) Ripk3iECKO and Ripk3WT mice were treated with tamoxifen at 8 weeks of age. At 12 weeks, mice were implanted with osmotic minipumps delivering bleomycin (BLM; 50 mg/kg) for 7 days. Lungs were harvested on day 32. Body weight and survival were monitored. Lung histopathology was assessed via H&E, CD45 (leukocyte marker), and a-smooth muscle actin (a-SMA; myofibroblast marker) staining.Results All groups showed transient weight lost post-BLM, most severe in males: Ripk3iECKO M (-19.9%), Ripk3WT M (-23.5%), Ripk3iECKO F (-14.6%), and Ripk3WT F (-17.3%). Survival at day 32 was 100% for Ripk3iECKO F and 83% for Ripk3WT F, while only 49% of Ripk3iECKO M and 37% of Ripk3WT M survived. Histology revealed greater lung injury in Ripk3WT mice, with widespread alveolar loss, CD45+ leukocyte infiltration, and a-SMA+ myofibroblast accumulation, particularly in Ripk3WT M mice. In contrast, Ripk3iECKO F mice showed reduced inflammation and fibrosis, and pathology mostly limited to subpleural regions.Conclusions Our preliminary data indicate that endothelial-specific RIPK3 deletion protects against BLM-induced lung inflammation and fibrosis. These protective effects were most pronounced in Ripk3iECKO F mice, underscoring the critical roles of both endothelial signaling and sex as modulators of disease severity. Ripk3WT M mice experienced the most pronounced weight loss, lowest survival and severe lung damage. Ongoing studies are focused on elucidating how RIPK3 regulates endothelial junction stability, vascular permeability, and immune cell recruitment. Additionally, transcriptomic and proteomic profiling will be employed to identify molecular pathways through which RIPK3 modulates endothelial function. These efforts aim to uncover novel therapeutic targets to preserve vascular integrity and guide the development of endothelium-focused treatments for SSc-ILD, ultimately improving outcomes for patients with this severe disease.