Abstract
The fusion of human serum albumin with human lactoferrin (hLF‐HSA) exerts strong anti‐migratory effects in human lung adenocarcinoma cells through matrix metalloproteinase 1 (MMP1) downregulation. We demonstrate that hLF‐HSA disrupts organelle pH homeostasis via Na
+
/H
+
exchanger 7 (NHE7) upregulation, inducing organelle alkalization in the Golgi apparatus. This organelle dysfunction alters the Golgi‐mediated secretome, leading to MMP1 downregulation and suppression of cell migration. hLF‐HSA‐induced MMP1 downregulation also reverses epithelial‐mesenchymal transition (EMT), further suppressing migration. Additionally, hLF‐HSA‐driven activation of caveolae‐mediated endocytosis (CavME) signaling downregulated MMP1 expression without NHE7 upregulation. These findings highlight that hLF‐HSA–mediated disruption of organelle pH regulation and CavME activation represents a potential strategy to suppress cancer cell migration.
Impact statement
This work reveals a previously unrecognized link between organelle pH dysregulation and cancer cell migration. By identifying hLF‐HSA as a dual modulator of Golgi function and endocytic signaling, it provides a mechanistic basis for developing novel anti‐metastatic strategies targeting intracellular trafficking rather than cytotoxicity.