Calcium hydroxyapatite suppresses extracellular matrix-related gene expression by modulating Piezo1-associated Ca2+ signaling and PKA activity.

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition driven by sustained pro-fibrotic signaling and underlies a wide range of pathological conditions. Accordingly, strategies that broadly suppress ECM production are considered promising for the treatment of fibrosis. Although calcium hydroxyapatite (CaHA) is primarily used as a nanoparticle-based dermal filler, previous observations that it affects collagen production suggest its potential repurposing as a regulator of ECM-related programs. Here, we investigated the anti-fibrotic efficacy of CaHA and the signaling mechanisms underlying its effects. CaHA broadly suppressed ECM-related gene expression in fibroblasts, extending beyond collagen to multiple ECM components and associated regulatory factors. Mechanistically, CaHA attenuated Piezo1-associated Ca2+ signaling and was also associated with activation of the PKA pathway. Importantly, CaHA similarly reduced ECM-related gene expression in a fibrotic liver cell model, supporting the broader relevance of its anti-fibrotic activity. Together, these findings identify CaHA as a broad suppressor of ECM-related gene expression through modulation of Piezo1-associated Ca2+ signaling and PKA-associated pathways, and support its potential as an anti-fibrotic therapeutic strategy.