Approximately 60% of glaucoma patients have a family history. Family‐based studies indicate that relatives of glaucoma patients have a 10‐fold higher risk of developing glaucoma compared to the control population. Genetic mutations have been reported as potential contributing factors to pathogenesis of glaucoma. In this study, we reported a Chinese family that many members affected with primary open‐angle glaucoma carried a PAPPA2 c.392G>C heterozygous mutation. Western blotting results showed that this mutation decreased PAPPA2 protein level. Strikingly, we found PAPPA2 and its substrate IGFBP5 both expressed in human aqueous humor samples, and PAPPA2 levels significantly decreased in the POAG group accompanied with IGFBP5 levels increased in the POAG group. We also demonstrated that PAPPA2 cleaved IGFBP5 in vitro. We found that overexpressed IGFBP5 increased many fibrosis‐related gene expression through mRNA sequencing, western blotting, and immunofluorescence staining assays in primary human trabecular meshwork cells (HTMCs). More importantly, we found an inadequate dose of Pappa2 caused POAG‐like phenotypes in the mouse model. So, we proved the vital function of the eye local PAPPA2‐IGFBP5 axis in regulating extracellular matrix homeostasis and contributing to trabecular meshwork fibrosis and pathogenesis of POAG.

Cardiometabolic multimorbidity (CMM) is an increasingly significant global public health concern. It refers to the coexistence of two or more cardiometabol