Tetrasodium pyrophosphate (TSPP) is a widely used phosphate-based food additive that may contribute to exogenous inorganic phosphate exposure, however, its potential role in renal fibrosis remains poorly understood. This study investigated the molecular targets and mechanisms underlying TSPP-induced renal fibrosis using integrative network toxicology combined with experimental validation. Network toxicology identified 39 overlapping targets, which were mainly enriched in renal tubular ion transport, ion homeostasis, and mineral metabolism. Target prioritization and transcriptomic analysis further identified SLC5A2, a proximal tubular sodium-glucose cotransporter involved in tubular reabsorptive function, as a key candidate target. In HK-2 cells, exogenous TSPP at 5 μM suppressed SLC5A2 expression and induced inflammatory and profibrotic responses. Conversely, these effects were partially attenuated by SLC5A2 overexpression. These findings suggest that TSPP may contribute to renal fibrosis by downregulating SLC5A2 and disrupting proximal tubular transport homeostasis, thereby promoting inflammatory and profibrotic responses. Our results provide mechanistic insights into phosphate additive-associated renal fibrosis and highlight the chronic renal health risks associated with dietary and environmental exposure to TSPP, particularly in populations with impaired renal function.