Investigating prolactin-induced protein and its role in modulating the metabolic state of the keratoconus microenvironment

Keratoconus (KC) is a progressive corneal disorder characterized by thinning and irregular astigmatism, leading to visual impairment. This study investigates the role of Prolactin-Induced Protein (PIP), a 17-kDa glycoprotein significantly downregulated in KC subjects, in modulating corneal cellular metabolism. Using human corneal fibroblasts from healthy (HCFs) and KC (HKCs) subjects, we assessed the effects of exogenous PIP (50-500 ng/ mL) via targeted mass spectrometry and Seahorse bioenergetic analyses. Metabolomic profiling revealed that PIP significantly modulates various metabolites involved in multiple bioenergetic and oxidative stress related pathways including the Warburg effect and thiamine metabolism. Seahorse analysis revealed that when compared to HCFs, HKCs exhibit impaired ATP production from both oxidative phosphorylation and glycolysis. Notably, PIP treatment reversed this impairment and selectively enhanced mitochondrial function and glycolysis in HKCs without affecting HCFs. This study provides the first evidence of PIP's role in regulating energy metabolism in KC, suggesting its potential as a therapeutic target for addressing the metabolic dysfunction underlying KC pathogenesis.