Molecular mechanisms, therapeutic strategies, and inter-organ fibrosis crosstalk of Gla proteins in cardiovascular disease.

Gla proteins are a vitamin K-dependent family long studied for their roles in blood clotting and vascular calcification. This review examines their broader involvement in cardiovascular disease, particularly cardiac fibrosis. We highlight that their functions are context-dependent, varying with disease stage and cellular environment, and that several occur independently of γ-carboxylation, challenging the view that this modification is universally required for their function. By comparing fibrosis across the heart, lung, liver, and kidney, we distinguish shared from organ-specific mechanisms. Finally, we discuss prospective therapies, from vitamin K supplementation to receptor-targeted approaches, and the questions that remain before clinical translation.