Hallmarks of Sublethal Endothelial Injury Are Differentially Induced by Cuminum cyminum Extracts with Distinct Phytochemical Profiles

Cuminum cyminum (cumin) is widely used as a culinary spice and medicinal plant, yet its endothelial effects remain poorly defined, and viability-only toxicity tests may miss relevant changes. We evaluated whether four C. cyminum extracts (aqueous, methanolic, acetonic, hexane) induce sublethal endothelial injury (SEI), defined as preserved viability with functional, molecular, and morphological alterations. Human microvascular endothelial cells (HMEC-1) were exposed to increasing extract concentrations, and endothelial viability, migration, molecular responses, and cytomorphology were evaluated. Organic extracts (methanolic, acetonic, and hexane) induced endothelial stress and injury-related responses. Methanolic and acetonic extracts caused concentration- and time-dependent cytotoxicity, accompanied by reduced migration, stress-related gene modulation, and marked morphological damage, whereas the hexane extract induced pronounced cytomorphological disruption and strong NOS2 induction. In contrast, the aqueous extract exhibited minimal cytotoxicity and significantly enhanced endothelial migration, together with FGF2 upregulation and moderate NOS2 induction, consistent with a sublethal, pro-migratory phenotype. Overall, extract composition strongly influenced endothelial responses, demonstrating that SEI can occur in the absence of overt cytotoxicity and highlighting the need to incorporate functional endothelial endpoints into the safety evaluation of herbal and plant-derived extracts.