This study offers new insights into the dual role of secretory phospholipase A2 (sPLA2) in lymphedema, highlighting its impact on lymphatic endothelial cell (LEC) functionality. Through transcriptomic analyses and co-culture experiments, we observed that sPLA2 has both protective and detrimental effects on human LECs (HLECs), mediated by macrophage activation. Our findings reveal that while low levels of sPLA2 promote LEC health, excessive sPLA2 leads to dysfunction, emphasizing the significance of the sPLA2/PLA2R axis and arachidonic acid metabolism (AA) in lymphedema pathology. The study suggests targeting sPLA2 and its downstream pathways as a novel therapeutic strategy for lymphedema, aiming to mitigate its progression by safeguarding HLEC integrity. This research underscores the importance of balanced sPLA2 activity in maintaining lymphatic vessel health and presents a new avenue for lymphedema management and treatment.