Background <p>Autologous fat grafting is limited by unpredictable resorption and complications, largely due to inadequate revascularization and persistent inflammation. The molecular mechanisms underlying these processes remain poorly understood.</p> Methods <p>Human fat grafts were implanted into nude mice and harvested at days 3, 7, 14, 21, and 28 for RNA sequencing. Differentially expressed genes (DEGs) were identified and functionally annotated using GO and KEGG analyses. Key candidates were validated via RT-PCR.</p> Results <p>Human-derived RNA decreased sharply after day 3, indicating graft cell death. Grafts at day 3 showed upregulation of hypoxia-response pathways (HIF-1, glycolysis) and downregulation of oxidative metabolism and adipogenesis. Recipient-derived transcriptomes revealed sustained upregulation of angiogenesis and ECM-related genes (Fgf1, Plau, and Ccbe1) and downregulation of inflammatory genes (Ccr2 and Relt). Dynamic changes were most pronounced between days 3 and 14, followed by stabilization.</p> Conclusion <p>Early fat grafting is characterized by metabolic adaptation to hypoxia and active host-mediated angiogenesis and inflammation resolution. Key genes identified may serve as therapeutic targets to enhance graft survival. This study provides a temporal transcriptomic atlas that elucidates the molecular basis of graft integration.</p> No Level Assigned <p>This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266</p>